Compositions and methods of treatment for conditions responsive to testosterone elevation

ABSTRACT

This invention relates to methods and pharmaceutical compositions useful in the treatment of conditions that are responsive to the elevation of testosterone levels in the body and the use of estrogen agonists/antagonists for the manufacture of medicaments for the treatment of conditions that are responsive to the elevation of testosterone levels in the body. The compositions are comprised of an estrogen agonist/antagonist and a pharmaceutically acceptable vehicle, carrier or diluent. These compositions are effective in treating male subject sexual dysfunction and timidity in female subjects including post-menopausal women and are effective in increasing libido in female subjects including post-menopausal women. In the case of male subject sexual dysfunction, the compositions may also include a compound which is an elevator of cyclic guanosine 3′,5′-monophosphate (cGMP). Additionally, the compositions are effective in other conditions whose etiology is a result of testosterone deficiency or which can be ameliorated by increasing testosterone levels within the body. Methods of the invention include the treatment of conditions that are responsive to elevation of testosterone levels such as treating male subject sexual dysfunction and timidity in female subjects including post-menopausal women and the increase of libido of female subjects including post-menopausal women. The methods of treatment are effective while substantially reducing the concomitant liability of adverse effects associated with testosterone administration.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority of U.S. non-provisionalapplication Ser. No. 09/757,423, filed Jan. 10, 2001, which claimspriority of U.S. provisional application No. 60/175,704, filed Jan. 12,2000.

FIELD OF THE INVENTION

[0002] This invention relates to compositions and methods for treatingconditions responsive to testosterone administration including malesubject sexual dysfunction, lowered libido in female subjects includingpost-menopausal women and timidity in female subjects includingpost-menopausal women. The compositions and methods utilize estrogenagonist/antagonist compounds.

BACKGROUND OF THE INVENTION

[0003] Testosterone, the principal androgen, is synthesized in thetestis, the ovary, and the adrenal cortex. In the circulation,testosterone serves as a prohormone for the formation of two classes ofsteroids: 5α-reduced androgens, which act as the intracellular mediatorsof most androgen action, and estrogens, which enhance some androgeniceffects and block others. Thus the net effect of the action ofendogenous androgens is the sum of the effects of the secreted hormone(testosterone), its 5α-reduced metabolite (dihydrotestosterone, and itsestrogenic derivative (estradiol). Adequate amounts of these hormonesare required for proper physical development and physiologicalhomeostasis. When diminished or absent from the body, pathologicalconditions can arise in the body due to a testosterone deficiency whichare treatable by testosterone replacement. Additional conditions can betreated or ameliorated through the supplementation of endogenoustestosterone.

[0004] Conditions responsive to testosterone elevation may arise inwomen as a result of menopause. Menopause occurs naturally at an averageage of 50 to 51 years in the USA. As ovaries age, response to pituitarygonadotropins (follicle-stimulating hormone [FSH] and luteinizinghormone [LH]) decreases, initially resulting in shorter follicularphases (thus, shorter menstrual cycles), fewer ovulations, decreasedprogesterone production, and more irregularity in cycles. Eventually,the follicle fails to respond and does not produce estrogen. Thetransitional phase, during which a woman passes out of the reproductivestage, begins before menopause. It is termed the climacteric orperimenopause, although many persons refer to it as menopause.

[0005] Premature menopause refers to ovarian failure of unknown causethat occurs before age 40. It may be associated with smoking, living athigh altitude, or poor nutritional status. Artificial menopause mayresult from oophorectomy, chemotherapy, radiation of the pelvis, or anyprocess that impairs ovarian blood supply.

[0006] Symptoms of the climacteric range from nonexistent to severe. Hotflushes (flashes) and sweating secondary to vasomotor instability affect75% of women. Most women have hot flushes for more than 1 year, and 25to 50% for more than 5 years. The woman feels warm or hot and mayperspire, sometimes profusely. The skin, especially of the head andneck, becomes red and warm. The flush, which may last from 30 sec to 5min, may be followed by chills. Vasomotor symptoms of the hot flushcoincide with the onset of LH pulses, but not every increase in LH isassociated with a hot flush, suggesting that hypothalamic control of LHpulses is independent of that of flushes. This independence is confirmedby the occurrence of hot flushes in women who have had pituitary failureand do not secrete LH and/or FSH.

[0007] Psychologic and emotional symptoms—including fatigue,irritability, insomnia, inability to concentrate, depression, memoryloss, headache, anxiety, and nervousness and timidity can occur. Sleepdisruption by recurrent hot flushes contributes to fatigue andirritability. Intermittent dizziness, paresthesias, palpitations, andtachycardia may also occur. Nausea, constipation, diarrhea, arthralgia,myalgia, cold hands and feet, and weight gain are also common.

[0008] The large reduction in estrogen leads to profound changes in thelower genital tract; eg, the vaginal mucosa and vulvar skin becomethinner, the normal bacterial flora changes, and the labiaminora,clitoris, uterus, and ovaries decrease in size. Inflammation of thevaginal mucosa (atrophic vaginitis) can cause the mucosa to have astrawberry appearance and can lead to urinary frequency and urgency,vaginal dryness, and dyspareunia. Women tend to lose pelvic muscle toneand to develop urinary incontinence, cystitis, and vaginitis.

[0009] In men, conditions responsive to testosterone elevation may becaused by primary hypogonadism (congenital or acquired) includingtesticular failure due to cryptorchidism, bilateral torsion, orchitis,vanishing testis syndrome, or orchidectomy, Klinefelter's syndrome,chemotherapy, or toxic damage from alcohol or heavy metals. Also, inmen, these conditions may be caused by secondary, i.e.,hypogonadotropic, hypogonadism (congenital or acquired)—idiopathicgonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency,or pituitary-hypothalamic injury from tumors, trauma, or radiation.These men have low serum testosterone concentrations without associatedelevation in gonadotropins.

[0010] The sexual response cycle is mediated by a delicate, balancedinterplay between the sympathetic and parasympathetic nervous systems.Vasocongestion is largely mediated by parasympathetic (cholinergic)outflow; orgasm is predominantly sympathetic (adrenergic). Ejaculationis almost entirely sympathetic; emission involves sympathetic andparasympathetic stimulation. These responses are easily inhibited bycortical influences or by impaired hormonal, neural, or vascularmechanisms. β-Adrenergic blockers may desynchronize emission,ejaculation, and perineal muscle contractions during orgasm, andserotonin agonists frequently interfere with desire and orgasm.

[0011] Disorders of sexual response may involve one or more of thecycle's phases. Generally, both the subjective components of desire,arousal, and pleasure and the objective components of performance,vasocongestion, and orgasm are disturbed, although any may be affectedindependently.

[0012] Sexual dysfunctions may be lifelong (no effective performanceever, generally due to intrapsychic conflicts) or acquired (after aperiod of normal function); generalized or limited to certain situationsor certain partners; and total or partial.

[0013] Penile erection is initiated by neuropsychologic stimuli thatultimately produce vasodilation of the sinusoidal spaces and arterieswithin the paired corpora cavernosa. Erection is normally preceded bysexual desire (or libido), which is regulated in part byandrogen-dependent psychological factors. Although nocturnal and diurnalspontaneous erections are suppressed in men with androgen deficiency,erections may continue for long periods in response to erotic stimuli.Thus, continuing action of testicular androgens appears to be requiredfor normal libido but not for the erectile mechanism itself.

[0014] The penis is innervated by sympathetic, parasympathetic, andsomatic fibers. Somatic fibers in the dorsal nerve of the penis form theafferent limb of the erectile reflex by transmitting sensory impulsesfrom the penile skin and glans to the S2-S4 dorsal root ganglia via thepudendal nerve. Unlike the corpuscular-type endings in the penile shaftskin, most afferents in the glans terminate in free nerve endings. Theefferent limb begins with parasympathetic preganglionic fibers fromS2-S4 that pass in the pelvic nerves to the pelvic plexus. Sympatheticfibers emerging from the intermediolateral gray areas of T11-L2 travelthrough the paravertebral sympathetic chain ganglia, superiorhypogastric plexus, and hypogastric nerves to enter the pelvic plexusalong with parasympathetic fibers. Somatic efferent fibers from S3-S4that travel in the pudendal nerve to the ischiocavernosus andbulbocavernosus muscles and postganglionic sympathetic fibers thatinnervate the smooth muscle of the epididymis, vas deferens, seminalvesicle, and internal sphincter of the bladder mediate rhythmiccontraction of these structures at the time of ejaculation.

[0015] Autonomic nerve impulses, integrated in the pelvic plexus,project to the penis through the cavernous nerves that course along theposterolateral aspect of the prostate before penetrating the pelvicfloor muscles immediately lateral to the urethra. Distal to themembranous urethra, some fibers enter the corpus spongiosum, while theremainder enter the corpora cavernosa along with the terminal branchesof the pudendal artery and exiting cavernous veins.

[0016] The brain exerts an important modulatory influence over spinalreflex pathways that control penile function. A variety of visual,auditory, olfactory, and imaginative stimuli elicit erectile responsesthat involve cortical, thalamic, rhinencephalic, and limbic input to themedial preoptic-anterior hypothalamic area, which acts as an integratingcenter. Other areas of the brain, such as the amygdaloid complex, mayinhibit sexual function.

[0017] Although the parasympathetic nervous system is the primaryeffector of erection, the transformation of the penis to an erect organis a vascular phenomenon. In the flaccid state the arteries, arterioles,and sinusoidal spaces within the corpora cavernosa are constricted dueto sympathetic-mediated contraction of smooth muscle in the walls ofthese structures. The venules between the sinusoids and the dense tunicaalbuginea surrounding the cavernosa open freely to the emissary veins.Erection begins when relaxation of the sinusoidal smooth muscles leadsto dilation of the sinusoids and a decrease in peripheral resistance,causing a rapid increase in arterial blood flow through internalpudendal and cavernosa arteries. Expansion of the sinusoidal systemcompresses the venules against the interior surface of the tunicaalbuginea, resulting in venous occlusion. The increase in intracorporealpressure leads to rigidity; less than complete expansion of thesinusoidal spaces leads to less than complete rigidity.

[0018] Erection occurs when adrenergic-induced sinusoid tone isantagonized by sacral parasympathetic stimulation that producessinusoidal relaxation primarily by synthesis and release of thenonadrenergic-noncholinergic (NANC) neurotransmitter nitric oxide (NO).The contribution of acetylcholine-dependent release of NO from thevascular endothelium is uncertain. In vitro electrical stimulation ofisolated corpus cavernosum strips (with or without endothelium) producessinusoidal relaxation by release of neurotransmitters within nerveterminals that is resistant to adrenergic and cholinergic blockers.Inhibitors of the synthesis of NO or of guanosine monophosphate (GMP),as well as nitric oxide scavengers, block sinusoidal relaxation. Avariety of neuropeptides found in corporal tissues, including vasoactiveintestinal peptide (VIP) and calcitonin gene-related peptide (CGRP),produce tumescence when injected into the penis but have uncertainphysiologic roles. Elevators of cGMP stimulate or facilitate tumescence.Certain compounds that block or inhibit phosphodiesterase enzymes thatact on cGMP have been found to be an orally active therapy forimpotence. Norepinephrine plays an important role in the adrenergicmechanism of detumescence.

[0019] Seminal emission and ejaculation are under control of thesympathetic nervous system. Emission results fromalpha-adrenergic-mediated contraction of the epididymis, vas deferens,seminal vesicles, and prostate which causes seminal fluid to enter theprostatic urethra. Concomitant closure of the bladder neck preventsretrograde flow of semen into the bladder, and antegrade ejaculationresults from contraction of the muscles of the pelvic floor includingthe bulbocavernosus and ischiocavernosus muscles.

[0020] Orgasm is a psychosensory phenomenon in which the rhythmiccontraction of the pelvic muscles is perceived as pleasurable. Orgasmcan occur without either erection or ejaculation or in the presence ofretrograde ejaculation.

[0021] Detumescence after orgasm and ejaculation is incompletelyunderstood. Presumably, active tone in the vessels of the sinusoidalspaces is restored by contraction (probably adrenergic-mediated) ofsmooth muscles, which decreases the inflow of blood to the penis andpromotes emptying of the erectile tissue. Following orgasm, there is arefractory period that varies in duration with age, physical condition,and psychic factors and during which erection and ejaculation areinhibited (McConnell J. D. and Wilson J. D., Impotence, Chapter 51, inHarrison's Principles of Internal Medicine, 14th ed., 1998).

[0022] Men with sexual dysfunction present with a variety of complaints,either singly, or in combination: loss of desire (libido), inability toinitiate or maintain an erection, ejaculatory failure, prematureejaculation, or inability to achieve orgasm. Sexual dysfunction can besecondary to systemic disease or its treatment, to specific disorders ofthe urogenital or endocrine systems, or to psychological disturbance. Itwas previously thought that the majority of men with erectile impotencyhad a psychological etiology for the dysfunction, but it is now believedthat most impotent men have a component of underlying organic disease.Impotence is the failure to achieve erection, ejaculation, or both.

[0023] A decrease in sexual desire, or libido, may be due to androgendeficiency (arising from either pituitary or testicular disease),psychological disturbance, or to some types of prescribed or habituallyabused drugs. The possibility of androgen deficiency can be tested bymeasurement of plasma testosterone and gonadotropin. The minimal levelof testosterone required for normal erectile function remains unknown.Hypogonadism may also result in the absence of emission, secondary todecreased secretion of ejaculate by the seminal vesicles and prostate.

[0024] The organic causes of erectile impotence can be grouped intoendocrine, drug, local, neurologic, and vascular causes. With theexception of severe depression, men with psychogenic impotence usuallyhave normal nocturnal and early morning erections. From early childhoodthrough the eighth decade, erections occur during normal sleep. Thisphenomenon, termed nocturnal penile tumescence (NPT), occurs duringrapid eye movement sleep, and the total time of NPT averages 100 min pernight. Consequently, if the impotent man gives a history of rigiderections under any circumstances (often when awakening in the morning),the efferent neurologic and circulatory systems that mediate erectionare intact.

[0025] If the history of nocturnal erections is questionable,measurements of NPT can be made formally with the use of a strain gaugein a sleep laboratory, or informally attached to a recorder, by snapgauge or home monitor. Although false-negative and false-positiveresults are possible, this procedure helps to differentiate psychogenicand organic impotence. Patients with vasculogenic impotence may havesome degree of penile tumescence without the development of adequaterigidity, which may result in a false-positive NPT test. An alternativeto NTP testing is the visual sexual stimulation test, which utilizesvideotaped erotic material in a laboratory setting to monitor erectionby strain gauge.

[0026] For the treatment of male subject sexual dysfunction, thecompositions of the present invention can be administered either singlyor in combination with cGMP elevating agents. Agents which elevate cGMPlevels are well known and can work through any of several mechanisms.Agents which selectively inhibit an enzyme predominantly involved incGMP breakdown, for example a cGMP-dependent phosphodiesteraseconstitute one example.

[0027] In particular, cyclic guanosine 3′,5′-monophosphatephosphodiesterase (cGMP PDE) inhibitors are widely known ascardiovascular agents for the treatment of conditions such as angina,hypertension, and congestive heart failure. More recently cGMP PDEinhibitors capable of inhibiting type V phosphodiesterase (cGMP PDEV)have been found to be effective for the treatment of impotence,importantly by oral administration. See, for example, PCT/EP94/01580,published as WO 94/28902 which designates, inter alia, the UnitedStates, and which is herein incorporated by reference.

[0028] The compositions and methods of the present invention act tocure, ameliorate, or prevent pathological conditions that are responsiveto the elevation of testosterone levels within the body. Elevation oftestosterone in the body can typically be measured in the blood, serum,plasma or at the site of action. Not being bound by any single theory,it is believed that administration of the compositions of the inventionresults in an elevation of testosterone levels within the body to cure,ameliorate or prevent conditions responsive to such elevations oftestosterone levels.

SUMMARY OF THE INVENTION

[0029] This invention relates to pharmaceutical compositions useful inthe treatment of conditions that are responsive to the elevation oftestosterone levels in the body. The compositions are comprised of anestrogen agonist/antagonist and a pharmaceutically acceptable carrier,vehicle or diluent. These compositions are effective in treating malesubject sexual dysfunction and timidity in female subjects includingpost-menopausal women and are effective in increasing libido in femalesubjects including post-menopausal women. In the case of male subjectsexual dysfunction, the compositions may also include a compound whichis an elevator of cyclic guanosine 3′,5′-monophosphate (cGMP).Additionally, the compositions are effective in other conditions whoseetiology is a result of testosterone deficiency or which can beameliorated by increasing testosterone levels within the body.

[0030] A second aspect of the invention relates to methods of treatingconditions that are responsive to treatment which elevates testosteronelevels within the body. These methods include treatment of male subjectsexual dysfunction and timidity in female subjects includingpost-menopausal women and treatment which increases libido in femalesubjects including post-menopausal women. In the case of the treatmentof male subject sexual dysfunction, the method may include theco-administration of an elevator of cGMP.

[0031] A third aspect of the invention is that the compositions andmethods of treatment for conditions responsive to testosterone elevationsubstantially reduces the concomitant liability of adverse effectsassociated with testosterone administration.

[0032] As a fourth aspect, the present invention provides kits for useby a consumer afflicted with or susceptible to physical conditions thatare responsive to the elevation of testosterone levels in the body. Thekit comprises a) a pharmaceutical composition comprising an estrogenagonist/antagonist and a pharmaceutically acceptable carrier, vehicle ordiluent; and b) instructions describing a method of using thepharmaceutical composition for treating physical conditions that areresponsive to the elevation of testosterone levels in the body. Theinstructions may also indicate that the kit is for the treatment oftestosterone-responsive conditions while substantially reducing theconcomitant liability of adverse effects associated with testosteroneadministration. The conditions responsive to testosterone elevationinclude male subject sexual dysfunction and timidity in female subjectsincluding post-menopausal women and the increase of libido in femalesubjects including post-menopausal women. This invention also provides akit comprising a therapeutically effective amount of an estrogenagonist/antagonist and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form and, optionally, a) atherapeutically effective amount of a cGMP elevator and apharmaceutically acceptable carrier, vehicle or diluent in a second unitdosage form.

[0033] As a fifth aspect, the present invention provides for the use ofestrogen agonists/antagonists for the manufacture of a medicament forthe treatment of conditions that are responsive to treatment thatelevates testosterone levels within the body. These conditions includemale subject sexual dysfunction and timidity in female subjectsincluding post-menopausal women and the increase libido in femalesubjects including post-menopausal women and which may be treated by themedicament without the concomitant liability of adverse effectsassociated with testosterone administration.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention relates to compositions and methods for thetreatment of conditions responsive to testosterone elevation. Unlessotherwise specified, the following terms have the meanings as definedbelow:

[0035] “Treatment” as used herein includes preventative (e.g.,prophylactic), curative or palliative treatment and “treating” as usedherein also includes preventative, curative and pallative treatment.

[0036] A “subject” is an animal including the human species that istreatable with the compositions, methods and kits of the presentinvention. The term “subject” or “subjects” is intended to refer to boththe male and female gender unless one gender is specifically indicated.

[0037] “Co-administration” of a combination of a estrogenagonist/antagonist and/or a cGMP elevator means that these componentscan be administered together as a composition or as part of the same,unitary dosage form. “Co-administration” also includes administering aestrogen agonist/antagonist and/or a cGMP elevator separately but aspart of the same therapeutic treatment program or regimen. Thecomponents need not necessarily be administered at essentially the sametime, although they can if so desired. Thus “co-administration”includes, for example, administering a estrogen agonist/antagonistand/or a cGMP elevator as separate dosages or dosage forms, but at thesame time. “Co-administration” also includes separate administration atdifferent times and in any order. For example, where appropriate apatient may take one or more component(s) of the treatment in themorning and the one or more of the other component(s) at night.

[0038] “Conditions responsive to elevation of testosterone levels”include those conditions caused by testosterone deficiency. Inchildhood, androgen deficiency has few consequences, but if it occurs atthe expected time of puberty, secondary sexual development is impaired.Patients with hypogonadism have poor muscle development, a high-pitchedvoice, inadequate phallic and testicular growth, small scrotum, sparsepubic and axillary hair, and absent body hair. They may developgynecomastia and attain eunuchoidal body proportions because of delayedfusion of the epiphyses and continued long bone growth. In adulthood,androgen deficiency has varied manifestations depending on the degreeand length of deficiency. Decreased libido, potency, and overallstrength are common. Testicular atrophy, fine wrinkling of the skinaround the eyes and lips, and sparse body hair may occur withlong-standing hypogonadism. Osteopenia and gynecomastia may alsodevelop. Additional indications responsive to testosterone treatmentinclude decreased libido in female subjects including post-menopausalwomen, timidity in female subjects including post-menopausal women,stimulation of erythropoiesis and treatment of anemia, treatment ofhereditary angiomeurotic edema, short stature, carcinoma of the breast,stimulation of muscle growth and increase in nitrogen balance.

[0039] “Timidity” is further defined as inappropriate fearfulness ofdifficult circumstances or social settings or inappropriate shynessattributable to the post-menopausal condition. Timidity and other socialtendencies can be assessed using health-related quality of life (HRQL)measurement questionnaires implemented in a double-blindplacebo-controlled clinical study of suitable size. One HRQL instrumentis the MOS 36-Item Short Form Health Survey (MOS SF-36) which wasdeveloped by A. L. Stewart, R. Hays and J. E. Ware (Ware, J. E. andSherbourne C. D., Med Care; 30:473,1992, Stewart A. L., et al., JAMA;262:907, 1989, Tarlov A. R., et al., JAMA; 262:925, 1989, McHorney C.A., et al., Med Care; 32:40, 1994). The MOS SF-36 collects informationfrom the patient on the areas of physical functioning; role limitationsdue to physical health problems; bodily pain; social functioning;general mental health; role limitations due to emotional problems,vitality, energy or fatigue and general health perceptions. Another HRQLmeasurement instrument is the Nottingham Health Profile (Hunt S. M., etal., Soc Sci Med; 15 A:221, 1981, Hunt S. M., et al., J Royal Coll GenPract; 35:185, 1985)—a two section, 46 item scale that measuresphysical, social, and emotional health problems and their impact onfunctioning.

[0040] “Male subject sexual dysfunction” includes decreased libido(hypoactive sexual desire disorder) in which sexual fantasies and desirefor sexual activity are persistently or recurrently diminished orabsent, causing marked distress or interpersonal difficulties. Alsoincluded are male subject orgasmic disorder characterized by apersistent or recurrent delay in or absence of orgasm after normalsexual arousal, and decreased potency (erectile dysfunction).

[0041] “Decreased libido in female subjects including post-menopausalwomen” is a hypoactive sexual desire disorder, as defined in malesubject sexual disorder, in which sexual fantasies and desire for sexualactivity are persistently or recurrently diminished or absent in apost-menopausal woman.

[0042] “Adverse effects associated with testosterone” includepolycythemia (and increased risk of stroke), gynecomastia, prostaticenlargement, sodium and water retention, impairment of hepatic function,hypercholesteremia and suppression of high-density lipoproteinconcentrations.

[0043] The term “female subjects including post-menopausal women” isdefined to include female animals including humans and, among humans,not only women of advanced age who have passed through menopause, butalso women who have undergone hysterectomy or for some other reason havesuppressed estrogen production, such as those who have undergonelong-term administration of corticosteroids, suffer from Cushions'syndrome or have gonadal dysgenesis.

[0044] An “estrogen agonist/antagonist” is a compound that affects someof the same receptors that estrogen does, but not all, and in someinstances, it antagonises or blocks estrogen. It is also known as a“selective estrogen receptor modulator” (SERM). Estrogenagonists/antagonists may also be referred to as antiestrogens althoughthey have some estrogenic activity at some estrogen receptors. Estrogenagonists/antagonists are therefore not what are commonly referred to as“pure antiestrogens”. Antiestrogens that can also act as agonists arereferred to as Type I antiestrogens. Type I antiestrogens activate theestrogen receptor to bind tightly in the nucleus for a prolonged timebut with impaired receptor replenishment (Clark et al., Steroids 22:707,1973, Capony et al., Mol Cell Endocrinol, 3:233,1975).

[0045] Preferred estrogen agonists/antagonists of the present inventioninclude the compounds described in U.S. Pat. No. 5,552,412. Thosecompounds are described by formula (I) given below:

[0046] wherein:

[0047] A is selected from CH₂ and NR;

[0048] B, D and E are independently selected from CH and N;

[0049] Y is

[0050] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0051] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0052] (c) C₃-C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0053] (d) C₃-C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0054] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴;

[0055] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0056] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²— and —S(O)_(n)—, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0057] Z¹ is

[0058] (a) —(CH₂)_(p) W(CH₂)_(q)—;

[0059] (b) —O(CH₂)_(p) CR⁵R⁶—;

[0060] (c) —O(CH₂)_(p)W(CH₂)_(q)—;

[0061] (d) —OCHR²CHR³—; or

[0062] (e) —SCHR²CHR³—;

[0063] G is

[0064] (a) —NR⁷R⁸;

[0065]  wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂—; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0066] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0067] Z¹ and G in combination may be

[0068] W is

[0069] (a) —CH₂—;

[0070] (b) —CH═CH—;

[0071] (c) —O—;

[0072] (d) —NR²—;

[0073] (e) —S(O)_(n)—;

[0074] (g) —CR²(OH)—;

[0075] (h) —CONR²—;

[0076] (i) —NR²CO—;

[0077] (k) —C≡C—;

[0078] R is hydrogen or C₁-C₆ alkyl;

[0079] R² and R³ are independently

[0080] (a) hydrogen; or

[0081] (b) C₁-C₄ alkyl;

[0082] R⁴ is

[0083] (a) hydrogen;

[0084] (b) halogen;

[0085] (c) C₁-C₆ alkyl;

[0086] (d) C₁-C₄ alkoxy;

[0087] (e) C₁-C₄ acyloxy;

[0088] (f) C₁-C₄ alkylthio;

[0089] (g) C₁-C₄ alkylsulfinyl;

[0090] (h) C₁-C₄ alkylsulfonyl;

[0091] (i) hydroxy (C₁-C₄)alkyl;

[0092] (j) aryl (C₁-C₄)alkyl;

[0093] (k) —CO₂H;

[0094] (l) —CN;

[0095] (m) —CONHOR;

[0096] (n) —SO₂NHR;

[0097] (o)—NH₂;

[0098] (p) C₁-C₄ alkylamino;

[0099] (q) C₁-C₄ dialkylamino;

[0100] (r) —NHSO₂R;

[0101] (s) —NO₂;

[0102] (t) -aryl; or

[0103] (u) —OH;

[0104] R⁵ and R⁶ are independently C₁-C₈ alkyl or together form a C₃-C₁₀carbocyclic ring;

[0105] R⁷ and R⁸ are independently

[0106] (a) phenyl;

[0107] (b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated;

[0108] (c) a C₃-C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N— and —S—;

[0109] (d) H;

[0110] (e) C₁-C₆ alkyl; or

[0111] (f) form a 3 to 8 membered nitrogen containing ring with R⁵ orR⁶;

[0112] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁-C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0113] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0114] e is 0, 1 or 2;

[0115] m is 1, 2 or 3;

[0116] n is 0, 1 or 2;

[0117] p is 0, 1, 2 or 3;

[0118] q is 0, 1, 2 or 3;

[0119] and optical and geometric isomers thereof; and nontoxicpharmacologically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts and prodrugs thereof.

[0120] By halo is meant chloro, bromo, iodo, or fluoro or by halogen ismeant chlorine, bromine, iodine or fluorine.

[0121] By alkyl is meant straight chain or branched chain saturatedhydrocarbon. Exemplary of such alkyl groups (assuming the designatedlength encompasses the particular example) are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyland isohexyl.

[0122] By alkoxy is meant straight chain or branched chain saturatedalkyl bonded through an oxy. Exemplary of such alkoxy groups (assumingthe designated length encompasses the particular example) are methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy,pentoxy, isopentoxy, hexoxy and isohexoxy.

[0123] The parenthetical negative or positive sign used herein in thenomenclature denotes the direction plane polarized light is rotated bythe particular stereoisomer.

[0124] Additional preferred compounds of the invention are of theformula (IA):

[0125] wherein G is

[0126] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N.

[0127] Especially preferred compounds of the invention for thecompositions and methods are:

[0128]cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0129](−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0130]cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0131]cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

[0132]1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0133]cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;and

[0134]1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand pharmaceutically acceptable salts thereof. An especially preferredsalt of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olis the tartrate salt.

[0135] Other preferred estrogen agonists/antagonists are described inU.S. Pat. No. 5,047,431. The structure of these compounds is given byformula (II) below:

[0136] wherein

[0137] R^(1A) and R^(2A) may be the same or different provided that,when R^(1A) and R^(2A) are the same, each is a methyl or ethyl group,and, when R^(1A) and R^(2A) are different, one of them is a methyl orethyl group and the other is hydrogen or a benzyl group; andpharmaceutically acceptable salts and prodrugs thereof.

[0138] Additional preferred estrogen agonists/antagonists are tamoxifen:(ethanamine, 2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl,(Z)-2-, 2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and other compoundsas disclosed in U.S. Pat. No. 4,536,516; 4-hydroxy tamoxifen (i.e.,tamoxifen wherein the 2-phenyl moiety has a hydroxy group at the 4position) and other compounds as disclosed in U.S. Pat. No. 4,623,660;raloxifene: (methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-hydrochloride)and other compounds as disclosed in U.S. Pat. Nos. 4,418,068, 5,393,763,5,457,117, 5,478,847 and 5,641,790; toremifene: (ethanamine,2-[4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)-,2-hydroxy-1,2,3-propanetricarboxylate (1:1) and other compounds asdisclosed in U.S. Pat. Nos. 4,696,949 and 4,996,225; centchroman:1-[2-[[4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy]-ethyl]-pyrrolidine and othercompounds as disclosed in U.S. Pat. No. 3,822,287; idoxifene:pyrrolidine, 1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl]and other compounds as disclosed in U.S. Pat. No. 4,839,155;6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-oland other compounds as disclosed in U.S. Pat. No. 5,484,795; and{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanoneand other compounds as disclosed in published international applicationWO 95/10513. Other preferred compounds include GW 5638 and GW 7604. Thesynthesis of these compounds is described in Willson et al., J. Med.Chem., 1994;37:1550-1552.

[0139] Further preferred estrogen agonists/antagonists include EM-652(as shown in the formula designated herein as formula (III) and EM-800(as shown in the formula designated herein as formula (IV)). Thesynthesis of EM-652 and EM-800 and the activity of various enantiomersis described in Gauthier et al., J. Med. Chem., 1997;40:2117-2122.

[0140] Further preferred estrogen agonists/antagonists include TSE 424and other compounds disclosed in U.S. Pat. No. 5,998,402, U.S. Pat. No.5,985,910, U.S. Pat. No. 5,780,497, U.S. Pat. No. 5,880,137, andEuropean Patent Application EP 0802183 A1 including the compoundsdescribed by the formulae designated herein as formulae V and VI, below:

[0141] wherein:

[0142] R_(1B) is selected from H, OH or the C₁-C₁₂ esters (straightchain or branched) or C₁-C₁₂ (straight chain or branched or cyclic)alkyl ethers thereof, or halogens; or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether.

[0143] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH or the C₁-C₁₂ esters (straight chain or branched) orC₁-C₁₂ alkyl ethers (straight chain or branched or cyclic) thereof,halogens, or C₁-C₄ halogenated ethers including trifluoromethyl etherand trichloromethyl ether, cyano, C₁-C₆ alkyl (straight chain orbranched), or trifluoromethyl;

[0144] X_(A) is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0145] s is 2 or 3;

[0146] Y_(A) is selected from:

[0147] a) the moiety:

[0148]  wherein R_(7B) and R_(8B) are independently selected from thegroup of H, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆alkyl (straight chain or branched), C₁-C₆ alkoxy (straight chain orbranched), halogen, —OH, —CF₃, or —OCF₃;

[0149] b) a five-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR₁₁, —NH₂,C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0150] c) a six-membered saturated, unsaturated or partially unsaturatedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₀-C₄ alkyl)-, —N═, and —S(O)_(u)—, whereinu is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR₁, —NH₂,C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0151] d) a seven-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHRLB, —NH₂,C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or

[0152] e) a bicyclic heterocycle containing from 6-12 carbon atomseither bridged or fused and containing up to two heteroatoms selectedfrom the group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR_(1B)—,—NH₂, —N═, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B),—NHCOR_(1B), —NO₂, and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; and optical and geometric isomers thereof; and nontoxicpharmacologically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts, and prodrugs thereof.

[0153] The more preferred compounds of this invention are those havingthe general structures V or VI, above, wherein:

[0154] R_(1B) is selected from H, OH or the C₁-C₁₂ esters or alkylethers thereof, and halogen;

[0155] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH or the C₁-C₁₂ esters or alkyl ethers thereof,halogen, cyano, C₁-C₆ alkyl, or trihalomethyl, preferablytrifluoromethyl, with the proviso that, when R_(1B) is H, R_(2B) is notOH;

[0156] X_(A) is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0157] Y_(A) is the moiety:

[0158] R_(7B) and R_(8B) are selected independently from H, C₁-C₆ alkyl,or combined by —(CH₂)_(w)—, wherein w is an integer of from 2 to 6, soas to form a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄alkyl), —NH₂, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄alkyl), —CO(C₁-C₄alkyl), and —NO₂; and optical and geometricisomers thereof; and nontoxic pharmacologically acceptable acid additionsalts, N-oxides, esters, quaternary ammonium salts, and prodrugsthereof.

[0159] The rings formed by a concatenated R_(7B) and R_(8B), mentionedabove, may include, but are not limited to, aziridine, azetidine,pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneaminerings.

[0160] The most preferred compounds of structural formulas V and VI,above, are those wherein R_(1B) is OH; R_(2B)-R_(6B) are as definedabove; X_(A) is selected from the group of Cl, NO₂, CN, CF₃, or CH₃;Y_(A) is the moiety

[0161] and R_(7B) and R_(8B) are concatenated together as —(CH₂)_(t)—,wherein t is an integer of from 4 to 6, to form a ring optionallysubstituted by up to three subsituents selected from the group ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl,—NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl,—NHCO(C₁-C₄)alkyl, and —NO₂; and optical and geometric isomers thereof;and nontoxic pharmacologically acceptable acid addition salts, N-oxides,esters, quaternary ammonium salts, and prodrugs thereof.

[0162] Another preferred compound is TSE-424 as described by the formuladesignated herein as formula (Va) below:

[0163] The subject invention also includes isotopically-labeled estrogenagonists/antagonists, which are structurally identical to thosedisclosed above, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸Fand ³⁶Cl, respectively. Compounds of the present invention, prodrugsthereof, and pharmaceutically acceptable salts of said compounds or ofsaid prodrugs which contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out known or referenced proceduresand by substituting a readily available isotopically labeled reagent fora non-isotopically labeled reagent.

[0164] Pharmaceutical chemists will easily recognize thatphysiologically active compounds which have accessible hydroxy groupsare frequently administered in the form of pharmaceutically acceptableesters. The literature concerning such compounds, such as estradiol,provides a great number of instances of such esters.

[0165] The compounds of this invention are no exception in this respect,and can be effectively administered as an ester, formed on the hydroxygroups, just as one skilled in pharmaceutical chemistry would expect.While the mechanism has not yet been investigated, it is believed thatesters are metabolically cleaved in the body, and that the actual drug,which such form is administered, is the hydroxy compound itself. It ispossible, as has long been known in pharmaceutical chemistry, to adjustthe rate or duration of action of the compound by appropriate choices ofester groups.

[0166] Certain ester groups are preferred as constituents of thecompounds of this invention. The estrogen agonists/antagonists maycontain ester groups at various positions as defined herein above, wherethese groups are represented as —COOR⁹, R⁹ is C₁-C₁₄ alkyl, C₁-C₃chloroalkyl, C₁-C₃ fluoroalkyl, C₅-C₇ cycloalkyl, phenyl, or phenylmono- or disubstituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, nitro,chloro, fluoro or tri(chloro or fluoro)methyl.

[0167] As used herein, the term “effective amount” means an amount ofcompound of the compositions, kits and methods of the present inventionthat is capable of inhibiting the symptoms of the described pathologicalconditions. The specific dose of a compound administered according tothis invention will, of course, be determined by the particularcircumstances surrounding the case including, for example, the compoundadministered, the route of administration, the state of being of thepatient, and the severity of the pathological condition being treated.

[0168] The pharmaceutically acceptable acid addition salts of thecompounds of this invention may be formed of the compound itself, or ofany of its esters, and include the pharmaceutically acceptable saltswhich are often used in pharmaceutical chemistry. For example, salts maybe formed with inorganic or organic acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfonic acids including such agentsas naphthalenesulfonic, methanesulfonic and toluenesulfonic acids,sulfuric acid, nitric acid, phosphoric acid, tartaric acid, pyrosulfuricacid, metaphosphoric acid, succinic acid, formic acid, phthalic acid,lactic acid and the like, most preferable with hydrochloric acid, citricacid, benzoic acid, maleic acid, acetic acid and propionic acid. Apreferred salt of(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olis the D-(−)-tartrate salt.

[0169] The compounds of this invention, as discussed above, are veryoften administered in the form of acid addition salts. The salts areconveniently formed, as is usual in organic chemistry, by reacting thecompound of this invention with a suitable acid, such as have beendescribed above. The salts are quickly formed in high yields at moderatetemperatures, and often are prepared by merely isolating the compoundfrom a suitable acidic wash as the final step of the synthesis. Thesalt-forming acid is dissolved in an appropriate organic solvent, oraqueous organic solvent, such as an alkanol, ketone or ester. On theother hand, if the compound of this invention is desired in the freebase form, it is isolated from a basic final wash step, according to theusual practice. A preferred technique for preparing hydrochlorides is todissolve the free base in a suitable solvent and dry the solutionthoroughly, as over molecular sieves, before bubbling hydrogen chloridegas through it.

[0170] The dose of a compound of this invention to be administered to ahuman is rather widely variable and subject to the judgment of theattending physician. It should be noted that it may be necessary toadjust the dose of a compound when it is administered in the form of asalt, such as a tartrate, the salt forming moiety of which has anappreciable molecular weight. The general range of effectiveadministration rates of the compounds is from about 0.001 mg/day toabout 250 mg/day. A preferred rate range is from about 0.010 mg/day to200 mg/day. Of course, it is often practical to administer the dailydose of compound in portions, at various hours of the day. However, inany given case, the amount of compound administered will depend on suchfactors as the solubility of the active component, the formulation usedand the route of administration.

[0171] The route of administration of the compounds of this invention isnot critical. It is usually preferred to administer a compound orallyfor reasons of convenience. However, the compounds may equallyeffectively be administered percutaneously, or as suppositories forabsorption by the rectum or vagina, if desired in a given instance. Allof the usual types of compositions may be used, including tablets,chewable tablets, capsules, solutions, parenteral solutions, troches,suppositories and suspensions. Compositions are formulated to contain adaily dose, or a convenient fraction of daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid.

[0172] In general, all of the compositions are prepared according tomethods usual in pharmaceutical chemistry and by those procedureoutlined in the U.S. Patents referenced above.

[0173] Capsules are prepared by mixing the compound with a suitablediluent and filling the proper amount of the mixture in capsules. Theusual diluents include inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

[0174] Tablets are prepared by direct compression, by wet granulation,or by dry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0175] A lubricant may be necessary in a tablet formulation to preventthe tablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

[0176] Tablet disintegrators are substances which swell when wetted tobreak up the tablet and release the compound. They include starches,clays, celluloses, algins and gums, more particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used as well assodium lauryl sulfate.

[0177] Tablets are often coated with sugar as a flavor and sealant, orwith film-forming protecting agents to modify the dissolution propertiesof the tablet. The compounds may also be formulated as chewable tablets,by using large amounts of pleasant-tasting substances such as mannitolin the formulation, as is now well-established in the art.

[0178] When it is desired to administer a compound as a suppository, thetypical bases may be used. Cocoa butter is a traditional suppositorybase, which may be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

[0179] The effect of the compounds may be delayed or prolonged by properformulation. For example, a slowly soluble pellet of the compound may beprepared and incorporated in a tablet or capsule. The technique may beimproved by making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules maybe coated with a film which resists dissolution for a predictable periodof time. Even the parenteral preparations may be made long-acting, bydissolving or suspending the compound in oily or emulsified vehicleswhich allow it to disperse only slowly in the serum.

[0180] The term “prodrug” means compounds that are transformed in vivoto yield a compound of the present invention. The transformation mayoccur by various mechanisms, such as through hydrolysis in blood. A gooddiscussion of the use of prodrugs is provided by T. Higuchi and W.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

[0181] For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[0182] Similarly, if a compound of the present invention comprises analcohol functional group, a prodrug can be formed by the replacement ofthe hydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, ora-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0183] If a compound of the present invention comprises an aminefunctional group, a prodrug can be formed by the replacement of ahydrogen atom in the amine group with a group such as R^(X)-carbonyl,R^(X)O-carbonyl, NR^(X)R^(X)′-carbonyl where R^(X) and R^(X)′ are eachindependently ((C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or Rx-carbonylis a natural α-aminoacyl or natural α-aminoacyl-natural a-aminoacyl,—C(OH)C(O)OY^(X) wherein (Y^(X) is H, (C₁-C₆)alkyl or benzyl),C(OY^(X0)) Y^(X1) wherein Y^(X0) is (C₁-C₄) alkyl and Y_(X1) is((C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y^(X2)) Y^(X3) wherein Y^(X2) is H ormethyl and Y^(X3) is mono-N- or di-N,N-(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

[0184] For the treatment of male subject sexual dysfunction, cGMPelevator agents may be coadministered with the estrogenagonist/antagonists of the present invention either separately or in asingle composition.

[0185] Preferred as the cGMP elevator are cGMP PDE inhibitors. cGMP PDEinhibitors which are selective for cGMP PDEs rather than cyclicadenosine 3′,5′-monophosphate phosphodiesterases (cAMP PDEs) and/orwhich are selective inhibitors of the cGMP PDE_(V) isoenzyme areparticularly preferred. Such particularly preferred cGMP PDE inhibitorsare disclosed in U.S. Pat. Nos. 5,250,534; 5,346,901; 5,272,147, and inthe international patent application published as WO 94/28902designating, inter alia, the U.S., each of which is incorporated hereinby reference.

[0186] Preferred cGMP PDE_(V) inhibitors include compounds of formula(III):

[0187] wherein:

[0188] R^(1B) is H; C₁-C₃ alkyl; C₁-C₃ perfluoroalkyl; or C₃-C₅cycloalkyl;

[0189] R^(2B) is H; C₁-C₆ alkyl optionally substituted with C₃-C₆cycloalkyl; C₁-C₃ perfluoroalkyl; or C₃-C₆ cycloalkyl;

[0190] R³B is C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;C₁-C₆ perfluoroalkyl; C₃-C₅ cycloalkyl; C₃-C₆ alkenyl; or C₃-C₆ alkynyl;

[0191] R^(4B) is C₁-C₄ alkyl optionally substituted with OH,NR^(5B)R^(6B), CN, CONR⁵BR^(6B) or CO₂R^(7B); C₂-C₄ alkenyl optionallysubstituted with CN, CONR⁵BR^(6B) or CO₂R^(7B); C₂-C₄ alkanoyloptionally substituted with NR^(5B)R^(6B); (hydroxy)C₂-C₄ alkyloptionally substituted with NR^(5B)R^(6B); (C₂-C₃ alkoxy)C₁-C₂ alkyloptionally substituted with OH or NR^(5B)R^(6B); CONR^(5B)R⁶B CO₂R^(7B);halo; NR^(5B)R^(6B); NHSO₂NR^(5B)R^(6B); NHSO₂R^(8B); SO₂NR^(9B)R^(10B)or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl,thienyl or triazolyl any of which is optionally substituted with methyl;

[0192] R^(5B) and R^(6B) are each independently H or C₁-C₄ alkyl, ortogether with the nitrogen atom to which they are attached form apyrrolidinyl, piperidino, morpholino, 4-N(R^(11B))-piperazinyl orimidazolyl group wherein said group is optionally substituted withmethyl or OH;

[0193] R^(7B) is H or C₁-C₄ alkyl;

[0194] R^(8B) is C₁-C₃ alkyl optionally substituted with NR^(5B)R^(6B);

[0195] R^(9B) and R^(10B) together with the nitrogen atom to which theyare attached form a pyrrolidinyl, piperidino, morpholino or4-N(R^(12B))-piperazinyl group wherein said group is optionallysubstituted with C₁-C₄ alkyl, C₁-C₃ alkoxy, NR^(13B)R^(14B) orCONR^(13B)R^(14B);

[0196] R^(9B) is H; C₁-C₃ alkyl optionally substituted with phenyl;(hydroxy)C₂-C₃ alkyl; or C₁-C₄ alkanoyl;

[0197] R^(12B) is H; C₁-C₆ alkyl; (C₁-C₃ alkoxy)C₂-C₆ alkyl;(hydroxy)C₂-C₆ alkyl; (R^(13B)R^(14B)N)C₂-C₆ alkyl; (R¹³B R¹⁴NOC)C₁-C₆alkyl; CONR^(13B)R¹⁴B; CSNR^(13B)R^(14B); or C(NH)NR¹³BR^(14B); and

[0198] R^(13B) and R^(14B) are each independently H; C₁-C₄ alkyl; (C₁-C₃alkoxy)C₂-C₄ alkyl; or (hydroxy)C₂-C₄ alkyl;

[0199] or a pharmaceutically acceptable salt thereof;

[0200] or a pharmaceutically acceptable composition containing eitherentity.

[0201] Preferred cGMP PDE_(V) inhibitors include sildenafil (preferablythe citrate salt){1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-phenyl]sulfonyl]-4-methylpiperazine},which has the structure of formula (IV):

[0202] and pharmaceutically acceptable salts thereof, the compoundhaving the structure of formula (V):

[0203] and pharmaceutically acceptable salts thereof, and the compound,3-ethyl-5-{5-[(4-ethylpiperazino)sulphonyl]-2-(2-methoxyethoxy)pyrid-3-yl}-2-(2-pyridylmethyl)-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-7-oneof formula (VI) below:

[0204] The compound of formula (V) is disclosed, for example, in U.S.Pat. Nos. 5,272,147 and 5,426,107.

[0205] Additional suitable cGMP PDE_(V) inhibitors that can be used inthe present invention in combination with an estrogen agonist/antagonistinclude the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756;the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0526004; thepyrazolo [4,3-d]pyrimidin-7-ones disclosed in published internationalpatent application WO 93/06104; the isomeric pyrazolo[3,4-d]pyrimidin-4-ones disclosed in published international patentapplication WO 93/07149; the quinazolin-4-ones disclosed in publishedinternational patent application WO 93/12095; the pyrido[3,2-d]pyrimidin-4-ones disclosed in published international patentapplication WO 94/05661; the purin-6-ones disclosed in publishedinternational patent application WO 94/00453; the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international patentapplication WO 98/49166; the pyrazolo [4,3-d]pyrimidin-7-ones disclosedin published international patent application WO 99/54333; the pyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751; the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in published international patentapplication WO 00/24745; the pyrazolo [4,3-d]pyrimidin-4-ones disclosedin EP-A-0995750; the compounds disclosed in published internationalapplication WO 95/19978; the compounds disclosed in publishedinternational application WO 99/24433 and the compounds disclosed inpublished international application WO 93/07124.

[0206] Preferred type V phosphodiesterase inhibitors for the use in thepresent invention include:5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(see EP-A-0526004);

[0207]3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(see WO 99/54333);(+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,also known as3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 99/54333);5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,also known as1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine(see Example 1 hereinafter);

[0208]5-[(2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(see Example 2 hereinafter);

[0209]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(see Example 3 hereinafter);

[0210]5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(see Example 4 hereinafter);

[0211]5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(see Example 5 hereinafter);

[0212](6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione(IC-351), i.e., the compound of examples 78 and 95 of publishedinternational application WO 95/19978, as well as the compound ofexamples 1, 3, 7 and 8;

[0213]2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil) also known as1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine,i.e., the compound of examples 20, 19, 337 and 336 of publishedinternational application WO 99/24433; the compound of example 11 ofpublished international application WO 93/07124 (EISAI); and

[0214] compounds 3 and 14 from Rotella, D. P., J. Med. Chem., 2000,43,1257.

[0215] Additional cGMP PDE_(V) inhibitors useful in conjunction with thepresent invention include:4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone;1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylicacid, monosodium salt;(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one;furaziocillin;cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one;3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone;1-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylicacid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome);Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko;see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960(Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456(Bayer) and Sch-51866.

[0216] Preferably, the cGMP PDE_(V) inhibitors have an IC₅₀ for PDE_(V)at less than 100 nanomolar, more preferably, at less than 50 nanomolar,more preferably still at less than 10 nanomolar.

[0217] IC₅₀ values for the cGMP PDE_(V) inhibitors may be determinedusing established literature methodology, for example as described in EP0463756-B1 and EP 0526004-A1.

[0218] Preferably the cGMP PDE_(V) inhibitors used in the invention areselective for the PDE_(V) enzyme. Preferably they are selective overPDE_(III), more preferably over PDE_(III), and PDE_(IV). Preferably, thecGMP PDE_(V) inhibitors of the invention have a selectivity ratiogreater than 100 more preferably greater than 300, over PDE_(III), andmore preferably over PDE_(III), and PDE_(IV).

[0219] Selectivity ratios may readily be determined by the skilledperson. IC₅₀ values for the PDE_(III) and PDE_(IV) enzyme may bedetermined using established literature methodology, see S. A. Ballardet al,. Journal of Urology, 1998, vol.159, pages 2164-2171.

PDE_(V) SYNTHETIC EXAMPLES Example 12-(Methoxyethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0220]

[0221] A mixture of the product from stage i) below (0.75 mmol),potassium bis(trimethylsilyl)amide (298 mg, 1.50 mmol) and ethyl acetate(73 microlitres, 0.75 mmol) in ethanol (10 ml) was heated at 120° C. ina sealed vessel for 12 hours. The cooled mixture was partitioned betweenethyl acetate and aqueous sodium bicarbonate solution, and the layersseparated. The organic phase was dried (MgSO₄), and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol (98:2) aseluant to afford the title compound, 164 mg; Found: C, 53.18; H, 6.48;N, 18.14; C₂₃H₃₃N₇O₅S;0.20C₂H₅CO₂CH₃ requires C, 53.21; H, 6.49; N,18.25%; δ (CDCl₃): 1.04 (3H, t), 1.40 (3H, t), 1.58 (3H, t), 2.41 (2H,q), 2.57 (4H, m), 3.08 (2H, q), 3.14 (4H, m), 3.30 (3H, s), 3.92 (2H,t), 4.46 (2H, t), 4.75 (2H, q), 8.62 (1H, d), 9.04 (1H, d), 10.61 (1H,s); LRMS: m/z 520 (M+1)⁺; mp 161-162° C.

Preparation of Starting Materials

[0222] a) Pyridine-2-amino-5-sulphonic Acid

[0223] 2-Aminopyridine (80 g, 0.85 mol) was added portionwise over 30minutes to oleum (320 g) and the resulting solution heated at 140° C.for 4 hours. On cooling, the reaction was poured onto ice (200 g) andthe mixture stirred in an ice/salt bath for a further 2 hours. Theresulting suspension was filtered, the solid washed with ice water (200ml) and cold IMS (200 ml) and dried under suction to afford the titlecompound as a solid, 111.3 g; LRMS: m/z 175 (M+1)⁺.

[0224] b) Pyridine-2-amino-3-bromo-5-sulphonic Acid

[0225] Bromine (99 g, 0.62 mol) was added dropwise over an hour, to ahot solution of the product from stage a) (108 g, 0.62 mol) in water(600 ml) so as to maintain a steady reflux. Once the addition wascomplete the reaction was cooled and the resulting mixture filtered. Thesolid was washed with water and dried under suction to afford the titlecompound, 53.4 g; δ(DMSOd₆, 300 MHz): 8.08 (1H, s), 8.14 (1H, s); LRMS:m/z 253 (M)⁺.

[0226] c) Pyridine-3-bromo-2-chloro-5-sulphonyl Chloride

[0227] A solution of sodium nitrite (7.6 g, 110.0 mmol) in water (30 ml)was added dropwise to an ice-cooled solution of the product from stageb) (25.3 g, 100.0 mmol) in aqueous hydrochloric acid (115 ml, 20%), soas to maintain the temperature below 6° C. The reaction was stirred for30 minutes at 0° C. and for a further hour at room temperature. Thereaction mixture was evaporated under reduced pressure and the residuedried under vacuum at 70° C. for 72 hours. A mixture of this solid,phosphorus pentachloride (30.0 g, 144 mmol) and phosphorus oxychloride(1 ml, 10.8 mmol) was heated at 125° C. for 3 hours, and then cooled.The reaction mixture was poured onto ice (100 g) and the resulting solidfiltered, and washed with water. The product was dissolved indichloromethane, dried (MgSO₄), and evaporated under reduced pressure toafford the title compound as a yellow solid, 26.58 g; δ (CDCl₃, 300MHz): 8.46 (1H, s), 8.92 (1H, s).

[0228] d) 3-Bromo-2-chloro-5-(4-ethylpiperazin-1-ylsulphonyl)pyridine

[0229] A solution of 1-ethylpiperazine (11.3 ml, 89.0 mmol) andtriethylamine (12.5 ml, 89.0 mmol) in dichloromethane (150 ml) was addeddropwise to an ice-cooled solution of the product from stage c) (23.0 g,79.0 mmol) in dichloromethane (150 ml) and the reaction stirred at 0° C.for an hour. The reaction mixture was concentrated under reducedpressure and the residual brown oil was purified by columnchromatography on silica gel, using an elution gradient ofdichloromethane:methanol (99:1 to 97:3) to afford the title compound asan orange solid, 14.5 g; δ (CDCl₃, 300 MHz): 1.05 (3H, t), 2.42 (2H, q),2.55 (4H, m), 3.12 (4H, m), 8.24 (1H, s), 8.67 (1H, s).

[0230] e) 3-Bromo-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridine

[0231] A mixture of the product from stage d) (6.60 g, 17.9 mmol) andsodium ethoxide (6.09 g, 89.55 mmol) in ethanol (100 ml) was heatedunder reflux for 18 hours, then cooled. The reaction mixture wasconcentrated under reduced pressure, the residue partitioned betweenwater (100 ml) and ethyl acetate (100 ml), and the layers separated. Theaqueous phase was extracted with ethyl acetate (2×100 ml), the combinedorganic solutions dried (MgSO₄) and evaporated under reduced pressure toafford the title compound as a brown solid, 6.41 g; Found: C, 41.27; H,5.33; N, 11.11. C₁₃H₂₀BrN₃O₃S requires C, 41.35; H, 5.28; N, 10.99%; 6(CDCl₃, 300 MHz): 1.06 (3H, t), 1.48 (3H, t), 2.42 (2H, q), 2.56 (4H,m), 3.09 (4H, m), 4.54 (2H, q), 8.10 (1H, s), 8.46 (1H, s); LRMS: m/z378, 380 (M+1)⁺.

[0232] f) Pyridine2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)-3-carboxylic Acid EthylEster

[0233] A mixture of the product from stage e) (6.40 g, 16.92 mmol),triethylamine (12 ml, 86.1 mmol), and palladium (0)tris(triphenylphosphine) in ethanol (60 ml) was heated at 100° C. and200 psi, under a carbon monoxide atmosphere, for 18 hours, then cooled.The reaction mixture was evaporated under reduced pressure and theresidue purified by column chromatography on silica gel, using anelution gradient of dichloromethane:methanol (100:0 to 97:3) to affordthe title compound as an orange oil, 6.2 g; δ (CDCl₃, 300 MHz): 1.02(3H, t), 1.39 (3H, t), 1.45 (3H, t), 2.40 (2H, q), 2.54 (4H, m), 3.08(4H, m), 4.38 (2H, q), 4.55 (2H, q), 8.37 (1H, s), 8.62 (1H, s); LRMS:m/z 372 (M+1)⁺.

[0234] g) Pyridine2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)-3-carboxylic Acid

[0235] A mixture of the product from stage f) (4.96 g, 13.35 mmol) andaqueous sodium hydroxide solution (25 ml, 2N, 50.0 mmol) in ethanol (25ml) was stirred at room temperature for 2 hours. The reaction mixturewas concentrated under reduced pressure to half it's volume, washed withether and acidified to pH 5 using 4N hydrochloric acid. The aqueoussolution was extracted with dichloromethane (3×30 ml), the combinedorganic extracts dried (MgSO₄) and evaporated under reduced pressure toafford the title compound as a tan coloured solid, 4.02 g; 6 (DMSOd₆,300 MHz): 1.18 (3H, t), 1.37 (3H, t), 3.08 (2H, q), 3.17-3.35 (8H, m),4.52 (2H, q), 8.30 (1H, s), 8.70 (1H, s).

[0236] h)4-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-1H-3-ethylpyrazole-5-carboxamide

[0237] A solution of 4-amino-3-ethyl-1H-pyrazole-5-carboxamide (WO9849166) (9.2 g, 59.8 mmol) in N,N-dimethylformamide (60 ml) was addedto a solution of the product from stage g) (21.7 g, 62.9 mmol),1-hydroxybenzotriazole hydrate (10.1 g, 66.0 mmol) and triethylamine(13.15 ml, 94.3 mmol) in dichloromethane (240 ml).1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.26 g,69.2 mmol) was added and the reaction stirred at room temperature for 6hours. The dichloromethane was removed under reduced pressure, theremaining solution poured into ethyl acetate (400 ml), and this mixturewashed with aqueous sodium bicarbonate solution (400 ml). The resultingcrystalline precipitate was filtered, washed with ethyl acetate anddried under vacuum, to afford the title compound, as a white powder, 22g; δ (CDCl₃+1 drop DMSOd₆) 0.96 (3H, t), 1.18 (3H, t), 1.50 (3H, t),2.25-2.56 (6H, m), 2.84 (2H, q), 3.00 (4H, m), 4.70 (2H, q), 5.60 (1H,br s), 6.78 (1H, br s), 8.56 (1H, d), 8.76 (1H, d), 10.59 (1H, s),12.10-12.30 (1H, s); LRMS: m/z 480 (M+1)⁺.

[0238] i)2-Methoxyethyl-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0239] 1-Bromo-2-methoxyethane (1.72 mmol) was added to a solution ofthe product from stage h) (750 mg, 1.56 mmol) and caesium carbonate(1.12 g, 3.44 mmol) in N,N-dimethylformamide (15 ml) and the reactionstirred at 60° C. for 18 hours. The cooled mixture was partitionedbetween water and ethyl acetate, and the layers separated. The organiclayer was dried (MgSO₄), concentrated under reduced pressure andazeotroped with toluene to give a solid. This product was recrystallisedfrom ether, to afford the title compound as a white solid.

Example 25-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0240]

[0241] A mixture of the product from stage b) below (90 mg, 0.156 mmol),potassium bis(trimethylsilyl)amide (156 mg, 0.78 mmol) and ethyl acetate(14 mg, 0.156 mmol) in iso-propanol (12 ml) was stirred at 130° C. for 6hours in a sealed vessel. The cooled reaction mixture was poured intosaturated aqueous sodium bicarbonate solution (60 ml), and extractedwith ethyl acetate (60 ml). The combined organic extracts were dried(MgSO₄), and evaporated under reduced pressure to give a gum. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (92.6:6.6:0.6) to afford the titlecompound as a beige foam, 36 mg; 6 (CDCl₃) 1.01 (3H, t), 1.12 (6H, d),1.39 (3H, t), 1.94 (2H, m), 2.15 (2H, m), 2.22-2.44 (6H, m), 2.55 (6H,m), 3.02 (4H, m), 3.14 (4H, m), 4.22 (1H, m), 4.43 (2H, d), 8.60 (1H,d), 9.00 (1H, d), 10.54 (1H, s).

[0242] Preparation of Starting Materials

[0243] a)2-(1-tert-Butoxycarbonylpiperidin-4-yl)-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0244] Sodium hydride (64 mg, 60% dispersion in mineral oil, 1.6 mmol)was added to a solution of the product from Example 1, stage h) (1.46mmol) in tetrahydrofuran (10 ml), and the solution stirred for 10minutes. tert-Butyl 4-[(methylsulphonyl)oxy]-1-piperidinecarboxylate (WO9319059) (1.60 mmol) was added and the reaction stirred at 60° C. for 3days. The cooled mixture was partitioned between ethyl acetate andaqueous sodium bicarbonate solution, and the phases separated. Theaqueous layer was extracted with ethyl acetate, the combined organicsolutions dried (MgSO₄) and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel usingdichloromethane:methanol (98:2) as eluant to afford the title compoundas a white foam, 310 mg; δ (CDCl₃) 1.02 (3H, t), 1.23 (3H, t), 1.49 (9H,s), 1.57 (3H, m), 1.93 (2H, m), 2.16 (2H, m), 2.40 (2H, q), 2.54 (4H,m), 2.82-2.97 (4H, m), 3.10 (4H, m), 4.30 (3H, m), 4.79 (2H, q), 5.23(1H, s), 6.65 (1H, s), 8.63 (1H, d), 8.82 (1H, d), 10.57 (1H, s).

[0245] b)4-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(1-methylpiperidin-4-yl)pyrazole-5-carboxamide

[0246] Trifluoroacetic acid (1.5 ml) was added to a solution of theproduct from stage a) above (320 mg, 0.48 mmol) in dichloromethane (2ml) and the solution stirred at room temperature for 2½ hours. Thereaction mixture was evaporated under reduced pressure and the residuetriturated well with ether and dried under vacuum, to provide a whitesolid. Formaldehyde (217 microlitres, 37% aqueous, 2.90 mmol) was addedto a solution of the intermediate amine in dichloromethane (8 ml), andthe solution stirred vigorously for 30 minutes. Acetic acid (88microlitres, 1.69 mmol) was added, the solution stirred for a further 30minutes, then sodium triacetoxyborohydride (169 mg, 0.80 mmol) was addedand the reaction stirred at room temperature for 16 hours. The reactionmixture was poured into aqueous sodium bicarbonate solution, andextracted with ethyl acetate. The combined organic extracts were dried(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (91.75:7.5:0.75) as eluant toafford the title compound, 70 mg; δ (CDCl₃) 1.02 (3H, t), 1.22 (3H, t),1.58 (3H, t), 1.92 (2H, m), 2.14 (2H, m), 2.25-2.45 (7H, m), 2.54 (4H,m), 2.91 (2H, q), 2.99-3.16 (6H, m), 4.08 (1H, m), 4.78 (2H, q), 5.11(1H, brs), 6.65 (1H, brs), 8.63 (1H, d), 8.83 (1H, d), 10.53 (1H, s).

Example 35-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0247]

[0248] Pyridine (0.1 ml, 1.08 mmol) was added to a mixture of theproduct from stage a) below (250 mg, 0.54 mmol), copper (II) acetatemonohydrate (145 mg, 0.72 mmol), benzeneboronic acid (132 mg, 1.08 mmol)and 4 Å molecular sieves (392 mg) in dichloromethane (5 ml), and thereaction stirred at room temperature for 4 days. The reaction mixturewas filtered and the filtrate evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (97:3:0.5) as eluant, andtriturated with ether:hexane. The resulting solid was filtered andrecrystallised from iso-propanol:dichloromethane to give the titlecompound as a solid, 200 mg, δ (CDCl₃) 1.02 (3H, t), 1.47 (3H, t), 1.60(3H, t), 2.42 (2H, q), 2.58 (4H, m), 3.10 (2H, q), 3.17 (4H, m), 4.76(2H, q), 7.40 (1H, m), 7.51 (2H, m), 7.80 (2H, d), 8.67 (1H, d), 9.16(1H, s), 10.90 (1H, s); LRMS: m/z 538 (M+1)⁺.

[0249] Preparation of Starting Materials

[0250] a)5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0251] Potassium bis(trimethylsilyl)amide (8.28 g, 41.6 mmol) was addedto a solution of the product from Example 1, stage h) (10.0 g, 20.8mmol) and ethyl acetate (2 ml, 20 mmol) in ethanol (160 ml), and thereaction mixture heated at 120° C. for 12 hours in a sealed vessel. Thecooled mixture was evaporated under reduced pressure and the residue waspurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to give thetitle compound, 3.75 g; δ (CDCl₃) 1.03 (3H, t), 1.42 (3H, t), 1.60 (3H,t), 2.42 (2H, q), 2.58 (4H, m), 3.02 (2H, q), 3.16 (4H, m), 4.78 (2H,q), 8.66 (1H, d), 9.08 (1H, d), 11.00 (1H, s) 11.05-11.20 (1H, br s),LRMS: m/z 462 (M+1)⁺.

Example 45-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0252]

[0253] The product from stage h) below (0.23 mmol) was dissolved indichloromethane (10 ml) and acetone (0.01 ml) was added. After 30 minstirring sodium triacetoxyborohydride (0.51 mmol) was added and stirringcontinued for 14 h. Further acetone (0.01 ml) and sodiumtriacetoxyborohydride (0.51 mmol) were added and stirring continued fora further 4.5 h. Starting material still remained so further acetone(0.01 ml) and sodium triacetoxyborohydride (0.51 mmol) were added andstirring continued for a further 18 h. The reaction mixture was dilutedwith dichloromethane, washed with sodium bicarbonate solution thenbrine, dried (MgSO₄) and concentrated. Purification by flash columnchromatography (elution with 94:6:0.6 dichloromethane/methanol/0.88ammonia) gave the product as a solid, M.p. 162.8-163.6° C.; ¹H NMR (400MHz, MeOD): δ=1.00 (app. d, 9H), 1.30 (t, 3H), 1.84 (app. q, 2H), 2.60(s, 3H), 2.62-2.72 (m, 1H), 3.00-3.10 (q, 2H), 3.75 (t, 2H), 3.90 (t,2H), 4.50 (t, 2H), 5.25 (t, 1H), 8.70 (s, 1H), 8.90 (s, 1H); LRMS(TSP—positive ion) 439 (MH⁺); Anal. Found C, 61.92; H, 6.84; N, 18.70Calcd for C₂₃H₃₀0₃N₆.0.1CH₂Cl₂: C, 62.07; H, 6.81; N, 18.80.

[0254] Preparation of Starting Materials

[0255] a) 2-Propoxy-5-iodonicotinic Acid

[0256] N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100ml) and trifluoroacetic anhydride (25 ml) were added to2-propoxynicotinic acid (0.054 mol). The mixture was refluxed for 2.5 h,cooled and the solvents evaporated. The residue was extracted from waterwith ethyl acetate and the organics washed with water (twice) and brine(twice), dried (MgSO₄) and concentrated. The red residue was redissolvedin ethyl acetate washed with sodium thiosulfate solution (twice), water(twice), brine (twice), redried (MgSO₄) and concentrated to give thedesired product as a solid; ¹H NMR (300 MHz, CDCl₃): δ=1.05 (t, 3H),1.85-2.0 (m, 2H), 4.5 (t, 2H), 8.5 (s, 1H), 8.6 (s, 1H); Analysis: foundC, 35.16; H, 3.19; N, 4.46. Calcd for C₉H₁₀INO₃: C, 35.19; H, 3.28; N,4.56%; LRMS (TSP): 529.5 (MH⁺).

[0257] b)N-[3-(Aminocarbonyl)-5-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propoxy-nicotinamide

[0258] Oxalyl chloride (15.9 mmol) was added to a stirred solution ofthe product from stage a) (3.98 mmol) in dichloromethane (20 ml) and 3drops N,N-dimethylformamide added. After 2.5 h the solvent wasevaporated and the residue azeotroped 3 times with dichloromethane. Theresidue was resuspended in dichloromethane (4 ml) and added to a stirredmixture 4-amino-3-ethyl-1H-pyrazole-5-carboxamide (prepared as describedin WO 98/49166) (3.58 mmol) and triethylamine (7.97 mmol) indichloromethane (10 ml). After 1 h the solvent was evaporated and theresidue partitioned between ethyl acetate and water. The organic phasewas separated and washed with 2N HCl (twice), sodium bicarbonatesolution (twice) and brine before being dried (MgSO₄) and concentrated.The product was triturated with ether and filtered to give the titleproduct as a solid. The mother liquor was concentrated and purified byflash column chromatography (elution with 80% ethyl acetate:hexane) togive further product; ¹H NMR (300 MHz, d₄-MeOH): δ=1.0 (t, 3H), 1.25 (t,3H), 1.85-2.0 (m, 2H), 2.8 (q, 2H), 4.5 (t, 2H), 8.5 (s, 1H), 8.6 (s,1H); LRMS (TSP) 444 (MH⁺).

[0259] c) tert-Butyl 3-iodo-1-azetidinecarboxylate

[0260] A mixture of tert-butyl3-[(methylsulfonyl)oxy]-1-azetidinecarboxylate (prepared as described inSynlett 1998, 379; 5.0 g, 19.9 mmol), and potassium iodide (16.5 g, 99.4mmol) in N,N-dimethylformamide (25 ml), was heated at 100° C. for 42 h.The cooled mixture was partitioned between water and ethyl acetate, andthe layers separated. The organic phase was dried over MgSO₄,concentrated under reduced pressure and the residue azeotroped withxylene. The crude product was purified by flash column chromatography(dichloromethane as eluant) to give the title compound, 3.26 g; ¹H NMR(300 MHz, CDCl₃) δ=1.43 (s, 9H), 4.28 (m, 2H), 4.46 (m, 1H), 4.62 (m,2H); LRMS (TSP) 284 (MH)⁺

[0261] d) tert-Butyl3-(3-(aminocarbonyl)-5-ethyl-4-{[(5-iodo-2-propoxy-3-pyridinyl)carbonyl]amino}-1H-pyrazol-1-yl)-1-azetidinecarboxylate

[0262] Cesium carbonate (3.59 mmol) was added to a stirred solution ofthe product from stage b) (1.79 mmol) and the product from stage c)(2.15 mmol) in N,N-dimethylformamide (10 ml) under a nitrogenatmosphere. The mixture was heated at 80° C. for 24 h. The mixture wascooled and extracted from water with ethyl acetate. The organics weredried (MgSO₄) and concentrated to give a brown oil. Purification byflash column chromatography (gradient elution from 100% dichloromethaneto 90% dichloromethane/MeOH) gave the title product; ¹H NMR (400 MHz,DMSO): δ=0.95 (t, 3H), 1.05 (t, 3H), 1.40 (s, 9H), 1.78-1.88 (m, 2H),2.68 (q, 2H), 4.22-4.35 (m, 4H), 4.40 (t, 2H), 5.33 (t, 1H), 7.35 (bs,1H), 7.52 (bs, 1H), 8.40 (s, 1H), 8.55 (s, 1H), 10.10 (s, 1H); LRMS(TSP—positive ion) 373.2 (MH⁺—BOC and I); Anal. Found C, 45.11; H, 5.07;N, 13.56 Calcd for C₂₃H₃₁O₅N₆I. 0.2 DCM: C, 45.28; H, 5.14; N, 13.66.

[0263] e) tert-Butyl3-[3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate

[0264] The product from stage d) (28.4 mmol) was dissolved in n-propanol(200 ml), ethyl acetate (6 ml) and potassium t-butoxide (28.4 mmol) wereadded and the resultant mixture heated to reflux for 6 h. Additionalpotassium t-butoxide (14.2 mmol) was added and the mixture heated for afurther 2 h, after which the solvent was removed in vacuo. The residuewas partioned between water (50 ml) and methylene chloride (100 ml) andthe organic phase separated. The aqueous phase was extracted withdichloromethane (2×100 ml) and the combined organics dried over MgSO₄and reduced to a solid. Purification by column chromatography (elutionwith ethyl acetate) gave the title compound; ¹H NMR (400 MHz, CDCl₃):δ=1.05 (t, 3H), 1.30 (t, 3H), 1.43 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q,2H), 4.34 (t, 2H), 4.49 (t, 2H), 4.60 (br s, 2H), 5.20 (t, 1H), 8.41 (d,1H), 8.94 (s,1H), 10.75 (br s, 1H); LRMS (TSP—positive ion) 598.1(MNH₄+); Anal. Found C, 47.54; H, 5.02; N, 14.09 Calcd for C₂₃H₂₉0₄N₆1:C, 47.60; H, 5.04; N, 14.48.

[0265] f) tert-Butyl3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-1-azetidinecarboxylate

[0266] The product from stage e) (0.25 mmol) was suspended intriethylamine (2 ml) and trimethylsilylacetylene (0.39 mmol) andacetonitrile (2 ml to try and solubilise reactants). Pd(PPh₃)₂Cl₂ (0.006mmol) and cuprous iodide (0.006 mmol) were added and the reactionmixture stirred. After 1 h a further portion of trimethylsilylacetylene(0.19 mmol) was added and stirring continued for 2 h. The solvent wasevaporated and the residue partitioned between ethyl acetate and water.The organics were washed with brine, dried (MgSO₄) and concentrated.Purification by flash column chromatography (gradient elution from 100%dichloromethane to 99% dichloromethane/methanol) gave the titlecompound; ¹H NMR (400 MHz, MeOD): δ=0.25 (s, 9H), 1.05 (t, 3H), 1.31 (t,3H), 1.44 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q, 2H), 4.33 (t, 2H), 4.52(t, 2H), 4.54-4.80 (m, 2H), 5.18-5.25 (m, 1H), 8.32 (d, 1H), 8.74 (d,1H); LRMS (TSP—positive ion) 569 (MNH₄ ⁺), 452.0 (MH⁺); Anal. Found C,60.82; H, 6.90; N, 15.15 Calcd for C₂₈H₃₈O₄N₆Si: C, 61.07; H, 6.95; N,15.26.

[0267] g) tert-Butyl3-[3-ethyl-5-(5-ethynyl-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate

[0268] Potassium fluoride (0.38 mmol) was added to a stirred solution ofthe product of stage f) (0.19 mmol) in aqueous N,N-dimethylformamide (2ml N,N-dimethylformamide/0.2 ml water) at 0° C. After 10 min thereaction was allowed to warm to room temperature and stirred for 2 h.The reaction mixture was diluted with ethyl acetate and washed withwater, 1 N hydrochloric acid (3 times) and brine. The organic layer wasdried (MgSO₄) and concentrated to give the title compound as a solid; ¹HNMR (400 MHz, CDCl₃): δ=1.05 (t, 3H), 1.30 (t, 3H), 1.43 (s, 9H),1.88-2.00 (m, 2H), 3.00 (q, 2H), 3.19 (s, 1H), 4.35 (app t, 2H), 4.52(app t, 2H), 4.60-4.80 (br s, 2H), 5.22 (t, 1H), 8.39 (s, 1H), 8.80 (s,1H), 10.75 (br s, 1H); LRMS (TSP—positive ion) 496 (MNH₄ ⁺).

[0269] h)5-(5-Acetyl-2-propoxy-3-pyridinyl)-2-(3-azetidinyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0270] The product from stage g) (1.44 g, 3.0 mmol) in acetone (50 ml)and sulphuric acid (1 N, 3 ml) was treated with mercuric sulphate (268mg, 9.0 mmol) and heated to reflux for 6 h. The reaction mixture wasconcentrated to ˜20 ml in vacuo, poured into sodium bicarbonate (sat.aq., 20 ml) and extracted into methylene chloride (6×20 ml). Combinedorganics were washed with brine (20 ml), dried over MgSO₄, andconcentrated to a brown oil which was taken up in 40% trifluoroaceticacid in methylene chloride (50 ml) and water (1 ml) and stirred for 1 hat room temperature. After evaporation in vacuo, the residue waspurified by column chromatography (eluting with 95:5:1 methylenechloride:methanol:0.88 ammonia) to afford the title compound as a whitehydroscopic foam (1.65 g); m.p. 128.5-130.0° C.; ¹H NMR (400 MHz, MeOD):δ=1.00 (t, 3H), 1.30 (t, 3H), 1.79-1.90 (m, 2H), 2.60 (s, 3H), 3.00-3.10(q, 2H), 4.50 (t, 2H), 4.60-4.70 (m, 4H), 5.65-5.78 (m, 1H), 8.65 (s,1H), 8.90 (s, 1H); LRMS (TSP—positive ion) 397 (MH⁺).

Example 55-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0271]

[0272] The starting material (120 mg, 0.28 mmol) and cesium carbonate(274 mg, 0.84 mmol) were dissolved in n-butanol (4 ml), and heated at90° C. under nitrogen with molecular sieves for 96 h. The mixture wasthen partitioned between water (10 ml) and dichloromethane (10 ml). Theorganic layer was separated, and the aqueous layer extracted furtherwith dichloromethane (3×15 ml). The combined organic layers were dried(MgSO₄), and concentrated in vacuo. The crude product was purified byflash column chromatography (95:5:0.5-90:10:1 ethylacetate:methanol:0.88 NH₃ as eluents), to yield the title compound as acolourless glass (77 mg, 0.18 mmol); m.p. 91.6-93.7° C.; ¹H NMR (400MHz, CDCl₃): δ=1.00-1.05 (m, 6H), 1.38 (t, 3H), 1.50-1.62 (m, 2H),1.90-2.00 (m, 2H), 2.63 (s, 3H), 2.63-2.70 (m, 2H), 3.02 (q, 2H), 3.75(t, 2H), 3.90 (t, 2H), 4.68 (t, 2H), 5.10-5.20 (m, 1H), 8.84 (s, 1H),9.23 (s, 1H), 10.63 (br s, 1H); LRMS (TSP—positive ion) 439 (MH⁺); Anal.Found C, 60.73; H, 7.06; N, 18.03 Calcd for C₂₃H₃₀O₃N₆.0.2MeOH.0.1 DIPE:C, 60.88; H, 7.26; N, 17.90.

[0273] 1.1.1.1.1 Preparation of Starting Materials

[0274]5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-Pyrazolo[4,3-d]pyrimidin-7-one

[0275] Sodium cyanoborohydride (92 mg, 1.47 mmol) was added to a stirredsolution of the product from Example 4 stage h) (500 mg, 0.98 mmol) andsodium acetate (161 mg, 1.96 mmol) in methanol (10 ml) under nitrogen atroom temperature. After 1 h the mixture was poured into NaHCO₃ (sat.aq., 20 ml), and extracted with dichloromethane (3×15 ml). The combinedorganic layers were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by flash column chromatography (95:5:0.5-80:20:1ethyl acetate:methanol:0.88 NH₃ as eluent) to yield the title compoundas a white solid (140 mg, 0.33 mmol); ¹H NMR (400 MHz, CDCl₃): δ=0.97(t, 3H), 1.03 (t, 3H), 1.30 (t, 3H), 2.82-2.97 (m, 2H), 2.58-2.65 (m,5H), 2.98 (q, 2H), 3.68 (t, 2H), 3.85 (dd, 2H), 4.58 (dd, 2H), 5.05-5.17(m, 1H), 8.79 (s, 1H), 9.18 (s,1H), 10.62 (br s,1H); LRMS (TSP—positiveion) 426 (MH⁺).

[0276] Also preferred as CGMP PDE_(V) inhibitors are compounds disclosedin PCT/EP95/00183, published as WO 95/19978 and which designates, interalia, the United States, herein incorporated by reference, saidcompounds having the formula (VII):

[0277] and salts and solvates thereof, in which:

[0278] R^(0C) represents hydrogen, halogen or C₁-C₆alkyl,;

[0279] R^(1C) represents hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, haloC₁-C₆alkyl, C₃-C₈cycloalkyl,C₃-C₈cycloalkylC₁-C₃alkyl, arylC₁-C₃alkyl or heteroarylC₁-C₃alkyl;

[0280] R^(2C) represents an optionally substituted monocyclic aromaticring selected from benzene, thiophene, furan and pyridine or anoptionally substituted bicyclic ring

[0281] attached to the rest of the molecule via one of the benzene ringcarbon atoms and wherein the fused ring A is a 5- or 6-membered ringwhich may be saturated or partially or fully unsaturated and comprisescarbon atoms and optionally one or two heteroatoms selected from oxygen,sulphur and nitrogen; and R^(3C) represents hydrogen or C₁-C₃alkyl, orR^(1C) and R^(3C) together represent a 3- or 4-membered alkyl or alkenylring.

[0282] A preferred subset of compounds having formula VIIa (alsodisclosed in WO 95/19978) includes compounds of the formula:

[0283] and salts and solvates thereof, in which:

[0284] R^(0C) represents hydrogen, halogen or C₁-C₆alkyl;

[0285] R^(1C) represents hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl,C₃-C₈cycloalkyl, C₃-C₈cycloalkyl-C₁-C₃alkyl, arylC₁-C₃alkyl orheteroarylC₁-C₃alkyl; and

[0286] R^(2C) represents an optionally substituted monocyclic aromaticring selected from benzene, thiophene, furan and pyridine or anoptionally substituted bicyclic ring

[0287] attached to the rest of the molecule via one of the benzene ringcarbon atoms and wherein the fused ring A is a 5- or 6-membered ringwhich may be saturated or partially or fully unsaturated and comprisescarbon atoms and optionally one or two heteroatoms selected from oxygen,sulphur and nitrogen.

[0288] Oral daily dosages of the above cGMP elevators can range fromabout 1 mg to about 200 mg with a preferred range of from about 20 mg toabout 100 mg. Dosage is ad libitum from about 15 minutes to about 4hours prior to sexual activity. Dosages and timing of dosing can beadjusted for topical dosage forms such as creams or aerosols. cGMPelevators of the present invention include produgs, stereoisomers,hydrates, tautomers and salts of the described compounds. The cGMPelevators of the present invention may be formulated and administered asdescribed for the estrogen agonists/antagonists above.

[0289] The cGMP PDE inhibitors useful in this invention as cGMPelevators may be chosen from among any of those already known to the artor subsequently discovered and/or hereafter developed. Suitable cGMP PDEinhibitors include those disclosed in any of the following US patents:

[0290] a 5-substituted pyrazolo[4,3-d]pyrimidine-7-one as disclosed inU.S. Pat. No. 4,666,908;

[0291] a griseolic acid derivative as disclosed in any of U.S. Pat. Nos.4,634,706, 4,783,532, 5,498,819, 5,532,369, 5,556,975, and 5,616,600;

[0292] a 2-phenylpurinone derivative as disclosed in U.S. Pat. No.4,885,301;

[0293] a phenylpyridone derivative as disclosed in U.S. Pat. No.5,254,571;

[0294] a fused pyrimidine derivative as disclosed in U.S. Pat. No.5,047,404;

[0295] a condensed pyrimidine derivative as disclosed in U.S. Pat. No.5,075,310;

[0296] a pyrimidopyrimidine derivative as disclosed in U.S. Pat. No.5,162,316;

[0297] a purine compound as disclosed in U.S. Pat. No. 5,073,559;

[0298] a quinazoline derivative as disclosed in U.S. Pat. No. 5,147,875;

[0299] a phenylpyrimidone derivative as disclosed in U.S. Pat. No.5,118,686;

[0300] an imidazoquinoxalinone derivative or its aza analog as disclosedin U.S. Pat. Nos. 5,055,465 and 5,166,344;

[0301] a phenylpyrimidone derivative as disclosed in U.S. Pat. No.5,290,933;

[0302] a 4-aminoquinazoline derivative as disclosed in U.S. Pat. No.5,436,233 or 5,439,895;

[0303] a 4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline derivative asdisclosed in U.S. Pat. No. 5,405,847;

[0304] a polycyclic guanine derivative as disclosed in U.S. Pat. No.5,393,755;

[0305] a nitogenous heterocyclic compound as disclosed in U.S. Pat. No.5,576,322;

[0306] a quinazoline derivative as disclosed in U.S. Pat. No. 4,060,615;

[0307] a 6-heterocyclyl pyrazolo[3,4-d]pyrimidin-4-one as disclosed inU.S. Pat. No. 5,294,612; and

[0308] a 4-aminoquinazoline derivative as disclosed in U.S. Pat. No.5,436,233;

[0309] Other disclosures of cGMP PDE inhibitors include the following,all of which are herein incorporated by reference:

[0310] European patent Application (EPA) publication no. 0428268;

[0311] European patent 0442204;

[0312] International patent application publication no. WO 94/19351;

[0313] Japanese patent application 5-222000;

[0314] European Journal of Pharmacology, 251, (1994), 1;

[0315] International patent application publication no. WO 94/22855;

[0316] a pyrazolopyrimidine derivative as disclosed in European patentapplication 0636626;

[0317] a 4-aminopyrimidine derivative as disclosed in European patentapplication 0640599;

[0318] an imidazoquinazoline derivative as disclosed in Internationalpatent application WO95/06648;

[0319] an anthranilic acid derivative as disclosed in Internationalpatent application WO95/18097;

[0320] a tetracyclic derivative as disclosed in International patentapplication WO95/19978;

[0321] an imidazoquinazoline derivative as disclosed in European patentapplication 0668280; and

[0322] a quinazoline compound as disclosed in European patentapplication 0669324.

[0323] The cGMP PDE inhibition of a compound can be determined bystandard assays known to the art, for example as disclosed in U.S. Pat.No. 5,250,534. Compounds which are selective inhibitors of cGMP PDErelative to cAMP PDE are preferred, and determination of such compoundsis also taught in U.S. Pat. No. 5,250,534. Particularly preferred arecompounds which selectively inhibit the PDEV isoenzyme, as disclosed inthe aforementioned PCT/EP94/01580, published as WO 94/28902.

[0324] Advantageously, the present invention also provides a kit for useby a consumer afflicted with or susceptible to conditions responsive totestosterone elevation such as male subject sexual dysfunction,decreased libido in female subjects including post-menopausal women ortimidity in female subjects including post-menopausal women. The kitscomprise a) a pharmaceutical composition comprising an estrogenagonist/antagonist and a pharmaceutically acceptable carrier, vehicle ordiluent; and b) instructions describing a method of using thepharmaceutical composition for treating conditions that are responsiveto the elevation of testosterone levels in the body. The instructionsmay also indicate that the kit is for the treatment oftestosterone-responsive conditions while substantially reducing theconcomitant liability of adverse effects associated with testosteroneadministration. The conditions responsive to testosterone elevationinclude male subject sexual dysfunction and timidity in female subjectsincluding post-menopausal women and the increase of libido in femalesubjects including post-menopausal women. This invention also provides akit for the treatment of male subject sexual dysfunction comprising atherapeutically effective amount of an estrogen agonist/antagonist and apharmaceutically acceptable carrier, vehicle or diluent in a first unitdosage form and, optionally, a) a therapeutically effective amount of acGMP elevator either formulated in the same pharmaceutical compositionas the estrogen agonist/antagonist or formulated in a separatepharmaceutical composition with a pharmaceutically acceptable carrier,vehicle or diluent in a second unit dosage form.

[0325] A “kit” as used in the instant application includes a containerfor containing the pharmaceutical compositions and may also includedivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container employed can depend on the exact dosage form involved, forexample a conventional cardboard box would not generally be used to holda liquid suspension. It is feasible that more than one container can beused together in a single package to market a single dosage form. Forexample, tablets may be contained in a bottle that is in turn containedwithin a box. Typically the kit includes directions for theadministration of the separate components. The kit form is particularlyadvantageous when the separate components are preferably administered indifferent dosage forms (e.g., oral, topical, transdermal andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

[0326] An example of such a kit is a so-called blister pack. Blisterpacks are well known in the packaging industry and are being widely usedfor the packaging of pharmaceutical unit dosage forms (tablets,capsules, and the like). Blister packs generally consist of a sheet ofrelatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process recesses areformed in the plastic foil. The recesses have the size and shape ofindividual tablets or capsules to be packed or may have the size andshape to accommodate multiple tablets and/or capsules to be packed.Next, the tablets or capsules are placed in the recesses accordingly andthe sheet of relatively stiff material is sealed against the plasticfoil at the face of the foil which is opposite from the direction inwhich the recesses were formed. As a result, the tablets or capsules areindividually sealed or collectively sealed, as desired, in the recessesbetween the plastic foil and the sheet. Preferably the strength of thesheet is such that the tablets or capsules can be removed from theblister pack by manually applying pressure on the recesses whereby anopening is formed in the sheet at the place of the recess. The tablet orcapsule can then be removed via said opening.

[0327] It is desirable to provide a written memory aid, where thewritten memory aid is of the type containing information and/orinstructions for the physician, pharmacist or patient, e.g., in the formof numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested or a card which contains the same type ofinformation. Another example of such a memory aid is a calendar printedon the card e.g., as follows “First Week, Monday, Tuesday,” . . . etc .. . “Second Week, Monday, Tuesday, . . . ” etc. Other variations ofmemory aids will be readily apparent. A “daily dose” can be a singletablet or capsule or several tablets or capsules to be taken on a givenday. When the kit contains separate compositions, a daily dose ofanother one or more compositions of the kit can consist of one tablet orcapsule while a daily dose of another one or more compositions of thekit can consist of several tablets or capsules.

[0328] Another specific embodiment of a kit is a dispenser designed todispense the daily doses one at a time in the order of their intendeduse. Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter which indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

[0329] Methods of preparing various pharmaceutical compositions with acertain amount of active ingredient are known, or will be apparent inlight of this disclosure, to those skilled in this art. For examples,see Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa., 19th Edition (1995).

[0330] Pharmaceutical compositions according to the invention maycontain 0.001%-95% of the compound(s) of this invention. In any event,the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the condition or disease of the subject beingtreated.

[0331] Based on a reading of the present description and claims, certainmodifications to the compositions and methods described herein will beapparent to one of ordinary skill in the art. The claims appended heretoare intended to encompass these modifications.

[0332] All references and patents cited herein are incorporated byreference.

EXAMPLES Example 1 Measurement of Libido in Post-Menopausal Women

[0333] Enhancement of libido in post-menopausal women is evaluated in a12 week, placebo-controlled clinical study using the Women's HealthQuestionnaire (WHQ) as the measurement technique. Prior to thecommencement in the study, post-menopausal women are divided into twogroups of between 5 and 100 women in each group. One group is a placebocontrol group. The other group is a test group that receives apharmaceutical composition containing an estrogen agonist/antagonist. Atthe start of the study, all participants in both groups complete a WHQ.Participants in the control group receive a daily placebo composition.Participants in the test group receive a composition containing anestrogen agonist/antagonist. At the end of the study, participants inboth groups again complete the WHQ. The results of the WHQ from thecontrol group and the test group are then compared.

[0334] The Women's Health Questionnaire (WHQ) provides a detailedexamination of minor psychological and somatic symptoms experienced byper- and postmenopausal women (Hunter M., et al., Maturitas; 8: 217,1986). The WHQ is well documented in terms of reliability and validity.The questionnaire has 36 questions rated on four-point scales. Thehigher the score, the more pronounced is the distress and dysfunction.The 36 items combine into nine factors describing somatic symptoms,depressed mood, cognitive difficulties, anxiety/fear, sexualfunctioning, vasomotor symptoms, sleep problems, menstrual symptoms andattraction.

Example 2 Pharmacological Testing of Treatment for Male Subject SexualDysfunction

[0335] Adult male Sprague-Dawley rats are used for this study. Animalsare maintained singly in wire-bottom cages under controlled light (14hour light, 10 hour dark) and temperature. Animals receive Purina ratchow and tap water ad libitum.

[0336] All animals are tested for sexual behavior prior to orchidectomyand estrogen agonist/antagonist compound administration. The test maleis placed into a testing arena for 5 minutes prior to the introductionof a female via the top of the chamber. The stimulus female(ovariectomized) is rendered sexually receptive by a subcutaneous (s.c.)injection of 100 microgram of estradiol benzoate and 500 microgram ofprogesterone in 0.1 ml of corn oil, 48 and 4 hours prior to testing.Each mount, intromission and ejaculation is recorded. Each male istested every 5 days until four successive and consistent behavioralpatterns are achieved. In addition to copulatory tests, males are testedfor penile erection reflexes (Davidson et al, Physiology & Behavior;21:171, 1978). Erectile tests are performed 24 hours before copulatoryevents every 5 days. After copulatory behavior parameters are deemedsatisfactory, animals are bilaterally orchidectomized via a singlemid-ventral incision and rehoused for 28 days with no further behavioraltesting.

[0337] Rats are randomly divided among experimental groups, they receivea dose of estrogen agonist/antagonist or vehicle alone as a control viasingle or multiple tail vein injections prior to retesting. Testing isperformed as described above and the following parameters are calculatedfrom the record: mount latency (ML), the time from the introduction ofthe female to the initial mount or intromission; intromission latency(IL), the time from the introduction of the female to the firstintromission; ejaculation latency (EL), the time from the firstintromission to ejaculation; and postejaculatory interval (PEI), thetime from ejaculation to the first intromission of the next copulatoryseries. Tests are terminated and considered negative if intromissionlatency exceeds 15 minutes, ejaculation latency exceeds 30 minutes orpostejaculatory interval exceeds 15 minutes. Mounting frequency andintromission frequency are also assessed. Copulatory and penile reflextests are performed at 3, 7, 14, 21, 28, 35 and 42 days afteradministration of the compounds.

[0338] Records of the study are kept and at the end of the study theresults are compared. Activity of the compositions and methods of theinvention are illustrated by positive effects in the above assay.

Example 3 Testosterone Elevation

[0339] In a random, double-blind, parallel group, placebo-controlledstudy,3-{1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-but-enyl}-phenol wasadministered to men, aged 72 to 84 with below average serum testosteronelevels. Subjects received either placebo or3-{1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-but-enyl}-phenol as asequential escalating dose, with subjects receiving 20 mg daily for thefirst month, 40 mg daily for the second month, and 60 mg daily for thefinal four months (remainder) of the study. Total serum testosterone wasdetermined in the subjects at 4 weeks and at 2, 3 and 6 months. Theresults in Table 1 show a significant increase in total serumtestosterone in subjects receiving3-{1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-but-enyl}-phenol asthe treatment compound over subjects receiving placebo during the study(p=0.026). TABLE 1 Mean Percent Change From Baseline in TestosteronePlacebo Treatment Compound Standard Number of Standard Number of %Change Deviation Subjects % Change Deviation Subjects Week 4 13.23 38.9116 36.20 28.03 15 2 Months 15.78 31.97 17 44.45 25.85 13 3 Months 4.2926.49 17 41.47 29.00 14 6 Months 9.25 43.95 16 45.19 30.32 13

What is claimed is:
 1. A method of treating timidity in post menopausalwomen, enhancing libido in postmenopausal women, or treating male sexualdysfunction, the method comprising the step of: administering to apatient in need thereof an effective amount of an estrogenagonist/antagonist.
 2. A method as claimed in claim 1 further comprisingco-administering an effective amount of an elevator of cyclic guanosine3′,5′-monophosphate.
 3. A method as claimed in claim 1 wherein theestrogen agonist/antagonist is a compound of formula I

wherein: A is selected from CH₂ and NR; B, D and E are independentlyselected from CH and N; Y is (a) phenyl, optionally substituted with 1-3substituents independently selected from R⁴; (b) naphthyl, optionallysubstituted with 1-3 substituents independently selected from R⁴; (c)C₃-C₈ cycloalkyl, optionally substituted with 1-2 substituentsindependently selected from R⁴; (d) C₃-C₈ cycloalkenyl, optionallysubstituted with 1-2 substituents independently selected from R⁴; (e) afive membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)—, optionallysubstituted with 1-3 substituents independently selected from R⁴; (f) asix membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)— optionally substitutedwith 1-3 substituents independently selected from R⁴; or (g) a bicyclicring system consisting of a five or six membered heterocyclic ring fusedto a phenyl ring, said heterocyclic ring containing up to twoheteroatoms selected from the group consisting of —O—, —NR²— and—S(O)_(n)—, optionally substituted with 1-3 substituents independentlyselected from R⁴; Z¹ is (a) —(CH₂)_(p) W(CH₂)_(q)—; (b) —O(CH₂)_(p)CR⁵R⁶—; (c) —O(CH₂)_(p)W(CH₂)_(q)—; (d) —OCHR²CHR³—; or (e) —SCHR²CHR³—;G is (a) —NR⁷R⁸;

 wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or —CH₂—;optionally fused on adjacent carbon atoms with one or two phenyl ringsand, optionally independently substituted on carbon with one to threesubstituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or (c) a bicyclicamine containing five to twelve carbon atoms, either bridged or fusedand optionally substituted with 1-3 substituents independently selectedfrom R⁴; or Z¹ and G in combination may be

W is (a) —CH₂—; (b) —CH═CH—; (c) —O—; (d) —NR²—; (e) —S(O)_(n)—;

(g) —CR²(OH)—; (h) —CONR²—; (i) —NR²CO—;

(k) —C≡C—; R is hydrogen or C₁-C₆ alkyl; R² and R³ are independently (a)hydrogen; or (b) C₁-C₄ alkyl; R⁴ is (a) hydrogen; (b) halogen; (c) C₁-C₆alkyl; (d) C₁-C₄ alkoxy; (e) C₁-C₄ acyloxy; (f) C₁-C₄ alkylthio; (g)C₁-C₄ alkylsulfinyl; (h) C₁-C₄ alkylsulfonyl; (i) hydroxy (C₁-C₄)alkyl;(j) aryl (C₁-C₄)alkyl; (k) —CO₂H; (l) —CN; (m) —CONHOR; (n) —SO₂NHR; (o)—NH₂; (p) C₁-C₄ alkylamino; (q) C₁-C₄ dialkylamino; (r) —NHSO₂R; (s)—NO₂; (t) -aryl; or (u) —OH; R⁵ and R⁶ are independently C₁-C₈ alkyl ortogether form a C₃-C₁₀carbocyclic ring; R⁷ and R⁸ are independently (a)phenyl; (b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated; (c) aC₃-C₁₀ heterocyclic ring containing up to two heteroatoms, selected from—O—, —N— and —S—; (d) H; (e) C₀-C₆ alkyl; or (f) form a 3 to 8 memberednitrogen containing ring with R⁵ or R⁶; R⁷ and R⁸ in either linear orring form may optionally be substituted with up to three substituentsindependently selected from C₁-C₆ alkyl, halogen, alkoxy, hydroxy andcarboxy; a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring; e is 0, 1 or 2; m is 1, 2 or 3; n is 0, 1 or 2; p is 0, 1, 2 or 3;q is 0, 1, 2 or 3; or an optical or geometric isomer thereof; or anontoxic pharmacologically acceptable acid addition salt, N-oxide, esteror quaternary ammonium salt or prodrug thereof.
 4. A method as claimedin claim 1 wherein the estrogen agonist/antagonist is a compound offormula (IA):

wherein G is

R⁴ is H, OH, F, or Cl; and B and E are independently selected from CHand N.
 5. A method as claimed in claim 1 wherein the estrogenagonist/antagonist is a member of the group consisting ofcis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene,1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline,cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,and1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand optical or geometric isomers thereof; and nontoxic pharmacologicallyacceptable acid addition salts, N-oxides, esters, quaternary ammoniumsalts and prodrugs thereof.
 6. A method as claimed in claim 1 whereinthe estrogen agonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olor a nontoxic pharmacologically acceptable acid addition salt, N-oxide,ester, quaternary ammonium salt or prodrug thereof.
 7. A method asclaimed in claim 1 wherein said estrogen agonist/antagonist is acompound of formula II:

wherein R^(1A) and R^(2A) may be the same or different provided that,when R^(1A) and R^(2A) are the same, each is a methyl or ethyl group,and, when R^(1A) and R^(2A) are different, one of them is a methyl orethyl group and the other is hydrogen or a benzyl group; a compound offormulas III or IV:

a compound of formulas V and VI:

wherein: R_(1B) is selected from H, OH or the C₁-C₁₂ esters (straightchain or branched) or C₁-C₁₂ (straight chain or branched or cyclic)alkyl ethers thereof, or halogens; or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether. R_(2B), R_(3B), R_(4B),R_(5B), and R_(6B) are independently selected from H, OH or the C₁-C₁₂esters (straight chain or branched) or C₁-C₁₂ alkyl ethers (straightchain or branched or cyclic) thereof, halogens, or C₁-C₄ halogenatedethers including trifluoromethyl ether and trichloromethyl ether, cyano,C₁-C₆ alkyl (straight chain or branched), or trifluoromethyl; X_(A) isselected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl, andhalogen; s is 2 or 3; Y_(A) is selected from: a) the moiety:

 wherein R_(7B) and R_(8B) are independently selected from the group ofH, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; b) a five-membered saturated, unsaturatedor partially unsaturated heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═,and —S(O)_(u)—, wherein u is an integer of from 0-2, optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl,C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN,—CONHR_(1B), —NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B),—NHCOR_(1B), —NO₂, and phenyl optionally substituted with 1-3(C₁-C₄)alkyl; c) a six-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR₁, —NH₂,C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —N HCOR_(1B), —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; d) aseven-membered saturated, unsaturated or partially unsaturatedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, —N═, and —S(O)_(u)—, whereinu is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or e) abicyclic heterocycle containing from 6-12 carbon atoms either bridged orfused and containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₁-C₄ alkyl)-, and —S(O)_(u)—, wherein u isan integer of from 0-2, optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR_(1B)—, —NH₂, —N═, C₁-C₄alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, andphenyl optionally substituted with 1-3 (C₁-C₄) alkyl; or a componud offormula Va:

or optical or geometric isomers thereof; nontoxic pharmacologicallyacceptable acid addition salts, N-oxides, esters, quaternary ammoniumsalts; or prodrugs thereof.
 8. A method as claimed in claim 1 whereinsaid estrogen agonist/antagonist is a member selected from the groupconsisting of 4-hydroxy tamoxifen, raloxifene, toremifene, centchroman,idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-oland{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,GW 5638, GW 7604 and optical or geometric isomers thereof; and nontoxicpharmacologically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts and prodrugs thereof.
 9. A kit for treatingtimidity in post menopausal women, enhancing libido in postmenopausalwomen, or treating male sexual dysfunction, said kit comprising: a) apharmaceutical composition comprising an estrogen agonist/antagonist anda pharmaceutically acceptable vehicle, carrier or diluent; and b)instructions describing a method of using the pharmaceutical compositionto treat timidity in post menopausal women, enhance libido inpostmenopausal women or treat male sexual dysfunction.
 10. A kit asclaimed in claim 9 wherein the estrogen agonist/antagonist is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olor a nontoxic pharmacologically acceptable acid addition salt, N-oxide,ester, quaternary ammonium salt or prodrug thereof.
 11. A kit accordingto claim 9 further comprising an elevator of cyclic guanosine3′,5′-monophosphate.